WO2011057110A1

WO2011057110A1 - Gpr109a agonists for the treatment of cerebral ischemia

Info

Publication number: WO2011057110A1
Application number: PCT/US2010/055687
Authority: WO
Inventors: Markus Schwaninger; Sajjad Muhammad; Stefan Offermanns
Original assignee: Ruprecht-Karls-Universitat-Heidelberg
Priority date: 2009-11-06
Filing date: 2010-11-05
Publication date: 2011-05-12

Abstract

The present invention describes agonists for G Protein-coupled receptor 109A (GPR109A), compositions comprising the GPR109A agonists, and methods of using them. GPR109A agonists are used in methods for the treatment, prevention, and alleviation of an ischemic condition, such as cerebral ischemia.

Description

GPR109A AGONISTS FOR THE TREATMENT OF CEREBRAL

ISCHEMIA

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Ser. No.

61/259,062, filed on November 6, 2009, entitled "GPR109A Agonists For The Treatment Of Cerebral Ischemia," the entire content of which is hereby incorporated herein by reference for all purposes.

FIELD OF THE INVENTION

[0002] The present invention generally relates to the use of agonists of the high-affinity nicotinic receptor, G-coupled receptor 109A for the treatment, prevention and alleviation of an ischemic condition.

BACKGROUND OF THE INVENTION

[0003] The central nervous system (CNS) is comprised of the spinal cord, brain and retina, and contains trillions of nerve cells (neurons) that form networks capable of performing exceedingly complex functions. CNS neurons require energy to survive and perform their physiological functions, and it is generally recognized that the only source of energy for CNS neurons is the glucose, ketone bodies, and oxygen delivered by the blood. If the blood supply to all or any portion of the CNS is shut off, thereby depriving neurons of both oxygen and glucose (a condition known as ischemia), the deprived neurons rapidly degenerate. This condition of inadequate blood flow is commonly known in clinical neurology as a "stroke." If only the oxygen supply to the brain is interrupted, for example in asphyxia, suffocation or drowning, the condition is referred to as "hypoxia". If only the glucose supply is disrupted, for example when a diabetic takes too much insulin, the condition is called "hypoglycemia". All of these conditions involve energy deficiency and are recognized in clinical medicine as potential causes of brain damage.

[0004] There are two major types of stroke: ischemic stroke and hemorrhagic stroke.

Ischemic stroke occurs when a blood vessel that supplies blood to the brain is blocked by a blood clot. This may happen in two ways. A clot may form in an artery that is already very narrow. This is called a thrombus. If it completely blocks the artery, it is called a thrombotic stroke. A clot may also break off from somewhere in the body and travel up to the brain to block a smaller artery. This is called an embolism. It causes an embolic stroke. For example, an ischemic stroke may be caused by blood clot that forms in the heart. Such a clot may travel through the blood and can get stuck in the small arteries of the brain. This is known as a cerebral embolism. A hemorrhagic stroke occurs when a blood vessel in part of the brain becomes weak and bursts open, causing blood to leak into the brain. The flow of blood that occurs after the blood vessel ruptures damages brain cells.

[0005] Cerebral ischemia can result in varying degrees of tissue damage. Conditions of severe ischemia can produce irreversible injury, whereas in conditions of moderate ischemia, tissue damage may be reversible. The reversibility of tissue damage is important for the development of new therapeutic approaches for treatment.

[0006] Ischemia can be transient or permanent. Transient ischemia occurs e.g. during an episode of cardiac arrest. Permanent ischemia occurs e.g. following thrombotic or embolic occlusion of CNS blood vessels. If the ischemia is transient, the blood supply carrying oxygen and glucose to the CNS is restored immediately after the event and drugs that prevent neuronal degeneration or promote recovery from the ischemic insult can reach the ischemic tissue through the blood circulation. If the blood supply to a region of the brain is permanently blocked by a clot, it is not possible by current methods to prevent neuronal degeneration in the center of the ischemic area, because the ischemic tissue is permanently deprived of oxygen and glucose and drug supply to the ischemic tissue is only possible through collateral blood vessels. If blood flow is stopped for longer than a few seconds, the brain cannot get blood and oxygen. Brain cells can die, causing permanent damage.

However, there is a large tissue zone, known as the penumbra, at the circumferential margin of the ischemic area which receives blood from adjoining CNS regions, and this tissue zone is a potential target for drug therapy. Also, drugs that dissolve blood clots (thrombolytic agents, such as streptokinase and tissue plasminogen activator) are currently used for the treatment of ischemic stroke. However, the therapeutic time window is limited to about three hours after onset of symptoms. At later time points thrombolysis is no longer effective and may cause severe side effects.

[0007] Stroke is the third most common cause of death in the western world and the leading cause of disability in adults. In the United States 500,000 new strokes occur per year costing billions of dollars because of lost productivity and the need for rehabilitation. Many of those affected with strokes never recover full neurologic function or even a substantial measure of the neurologic function initially lost. [0008] About 95% of stroke patients cannot be treated effectively. Therapeutic options are limited to thrombolysis (attempting to provide blood supply to the afflicted area) that can be used only within the first three hours after onset of symptoms due to side effects such as intracerebral bleeding. Only about 5% of stroke patients are currently treated by

thrombolysis. Thrombolysis also has the risk of causing bleeding in the ischemic brain and can only be effective during a short time window. Despite achieving normal blood supply, often tissue damage in the brain cannot be prevented. Therefore, there is a need for other treatment options.

[0009] The development of therapeutic agents capable of preventing or treating the disease/disorder consequences of ischemic events, whether acute or chronic, would be highly desirable. Applicants surprisingly have discovered a hitherto unknown role for the high- affinity nicotinic receptor, G-coupled receptor 109 A (GPR109A; PumaG in mouse, HM74A in human, formerly also named HM74; Tunaru et al, 2003, Nat Med 9:352-325) in focal cerebral ischemia (also referred to herein as stroke).

BRIEF SUMMARY OF THE INVENTION

[0010] The role of GPR109A receptors in cerebral ischemia has been unknown. Applicants have demonstrated herein for the first time that the GPR109A receptor located on cells of the immune system is a target for a therapy of an ischemic condition, in particular for cerebral ischemia. More specifically, Applicants describe herein the use of nicotinic acid and GPR109A agonists for the treatment of cerebral ischemia and other ischemic conditions.

[0011] Without being bound by the theory, Applicants believe that GPR 109A agonists activate the GPR109A receptor and the immune cells carrying the GPR109A receptor on their cell surfaces subsequently inhibit the inflammation reaction caused by an ischemic event, such as cerebral ischemia.

[0012] The invention herein describes a method for the treatment or alleviation of an ischemic condition in a subject. In some embodiments, this method comprises the steps of (a) selecting a subject having an ischemic condition; and (b) administering to said subject a therapeutically effective amount of a G-protein coupled receptor 109A (GPR109A) agonist or a pharmaceutically acceptable salt or solvate thereof. Thereby, the ischemic condition is treated or alleviated.

[0013] In some embodiments the method of or the treatment or alleviation of an ischemic condition in a subject further comprises the step of:(c) administering to said subject (i) an agent having neurotrophic activity selected from the group consisting of NGF, BFNF, ADNF, and GDNF or (ii) a compound that enhances the neurotrophic activity of (i).

[0014] In some embodiments the method of or the treatment or alleviation of an ischemic condition in subject further comprises the step (c) administering to said subject (i) a lipid modifying compound or (ii) an active agent.

[0015] An ischemic condition treated or alleviated by a method of the present invention may result from coronary artery bypass graft surgery, cerebral ischemia, focal cerebral infarction, cerebral hemorrhage, hemorrhage infarction, hypertensive hemorrhage, intracranial vascular hemorrhage, subarachnoid hemorrhage, hypertensive encephalopathy, carotid stenosis or occlusion, cardiogenic thromboembolism, spinal stroke, spinal cord injury, atherosclerosis, vasculitis, macular degeneration, myocardial infarction, cardiac ischemia or supraventricular tachyarrhythmia. A preferred ischemic condition is cerebral ischemia.

[0016] The invention described herein also provides methods for treating a subject having a high risk for a stroke. In some embodiments, this method comprises the steps of: (a) selecting a subject having a high risk for a stroke and (b) administering to said subject a therapeutically effective amount of a G-protein coupled receptor 109A (GPR10 A) agonist or a pharmaceutically acceptable salt or solvate thereof.

[0017] The subject may have experienced a prior ischemic event. In some embodiments, the subject has one or more risk factor selected from the group consisting of arterial hypertension, hypercholesterolemia, diabetes, smoking, auricular fibrillation, an embolic heart disease, and increasing age.

[0018] The invention described herein also provides methods for decreasing the severity of an infarct in a subject afflicted with a cerebral ischemia. In some embodiments, this method comprises the steps of: (a) selecting a subject having a cerebral ischemia, (b) determining the severity of an infarct, and (c) administering to said subject a therapeutically effective amount of a G-protein coupled receptor 109A (GPR109A) agonist or a pharmaceutically acceptable salt or solvate thereof. Jhereby, the severity of the infarct is decreased.

[0019] The invention described herein further provides for the use of a GPR109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the treatment or alleviation of an ischemic condition.

[0020] The invention described herein further provides for the use of a GPR109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the treatment of a subject having a high risk for a stroke.

[0021] The invention described herein further provides for the use of a GPR109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for decreasing the severity of an infarct in a subject afflicted with cerebral ischemia.

[0022] Various GPR109 A agonists may be used to practice methods of the present invention or in the making of a medicament.. In some emodiments, a GPR109A agonist is a compound represented by Formula (I):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0023] In some emodiments, a GPR109A agonist is a compound represented by Formula (II):

[0024] In some emodiments, a GPR109 A agonist is a compound represented by Formula (III):

[0025] In some emodiments, a GPR109A agonist is a compound represented by Formula (IV):

wherein R is

[0026] In some emodiments, a GPR109A agonist is a compound represented by Formula (V):

wherein R is

[0027] In some emodiments, a GPR109A agonist is a compound represented by Formula (VI):

[0028] In some emodiments, a GPR109A agonist is a compound represented by Formula (VII):

[0029] In some emodiments, a GPR109A agonist is a compound represented by Formula (VIII):

[0030] In some emodiments, a GPR109A agonist is a compound represented by Formula (IX):

[0031] In some emodiments, a GPR109A agonist is a compound represented by Formula (X):

[0032] In some emodiments, a GPR109A agonist is a compound represented by Formula (XI):

[0033] In some emodiments, a GPR109A agonist is a compound represented by Formula (XII):

[0034] In some emodiments, a GPR109A agonist is a compound represented by Formula (XIII):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof; wherein

Ri is Ph, vinyl, Ethyl, 1 -spiro, spirocyc, 1 -cyclopentenyl, 1 -cyclohexenyl, 3- pyrimidine. 4-pyrimidine, 2-furan, 2,5-diCl-Ph, 2,4-diF-Ph, 3,4-diF-Ph, 2,6-diF-Ph, 3,5-diF Ph, 2-F-Ph, 4-F-Ph. 3-F-Ph, 3-CI-Ph, 3-Br-Ph, 3-I-Ph, 3-Me-Ph, 3-Et-Ph, 3-CF3-Ph, or 3- OMe-Ph; and

R₂ is Me, Et, indane, or lopetane.

[0035] In some emodiments, a GPR109A agonist is a compound represented by Formula (XIV):

Ri is 2-thienyl, 5-Cl-2-thienyl, 5-Me-2-thienyl, 4-Br-2-thienyl, 4-Me-2- thienyl, 4-Br-5-Me-2-thienyl, 3-thienyl, 5-Cl-3-thienyl, 5-Br-3-thienyl, or 5-Me-3-thienyl.

[0036] In some emodiments, a GPR109A agonist is a compound represented by Formula (XXI):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof; wherein:

X represents a nitrogen or carbon atom;

Y represents C or N, such that when Y represents nitrogen, the nitrogen atom may be optionally substituted with H or R⁶ wherein:

R⁶ represents alkyl optionally substituted with 1-3 halo groups;

and when Y represents a carbon atom, the carbon atom may be substituted with hydrogen or halo;

p represents an integer of from 1 to 2, such that when p represents 2, no more than one Y represents a nitrogen atom;

the dashed lines represent optional bonds;

when the dashed line to Z represents a bond that is present, Z is selected from O, S and NH and the dashed line to (Y)_p represents a bond that is absent;

when the dashed line to Z represents a bond that is absent, the dashed line to (Y)_p represents a bond that is present and Z represents a group selected from OH, SH, NH₂, C0₂H and SO3H;

ring B represents phenyl, a 5-7 membered carbocycle, or a 5-6 membered heteroaryl, heterocyclic or partially aromatic heterocyclic group, said heteroaryl, heterocyclic and partially aromatic heterocyclic groups containing at least one heteroatom selected from O, S and N, and optionally containing 1 additional N atom, with up to 2 heteroatoms being present;

each R⁴ is H or halo, or is selected from the group consisting of:

a) a phenyl or a 5-6 membered heteroaryl group containing 1 heteroatom selected from O, S and N, and optionally containing 1 -3 additional N atoms, said phenyl and heteroaryl groups being optionally substituted with 1 -3 substituents, 1 -3 of which are halo, and 0-1 of which are selected from: OH, NH₂, Ci.₃alkyl, Ci.₃alkoxy, haloCi_-3alkyl and haloC].3alkoxy; and

(b) Ci alkyl optionally substituted with 1 -3 substituent groups, 1-3 of which are halo atoms, and 0- 1 of which are selected from the group consisting of: OH, OCi alkyl, NH_2> NHC,.₃alkyl, N(C_1-3alkyl)₂, CN, N0₂, Hetcy, phenyl and a 5-6 membered heteroaryl group containing 1 heteroatom selected from O, S and N, and optionally containing 1 -3 additional N atoms, said phenyl and heteroaryl groups being optionally substituted with 1-3 substituents, 1-3 of which are halo, and 0-1 of which are selected from: OH, NH₂, Ci alkyl, Ci.₃alkoxy, haloC|.₃alkyl and haloCi.₃alkoxy;

ring A represents a 6- 10 membered ary 1, a 5- 13 membered heteroaryl or a partially aromatic heterocyclic group, said heteroaryl and partially aromatic heterocyclic group containing at least one heteroatom selected from O, S and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1 -3 additional N atoms, with up to 5 heteroatoms being present;

R² and R³ are independently H, Ci.₃alkyl, haloC].₃alkyl, OC]_-3alkyl, haloCi.

₃alkoxy, OH, NH₂ or F;

n represents an integer of from 1 to 5;

each R¹ is H or is selected from the group consisting of:

a) halo, OH, C0₂H, CN, NH_2, S(O)_0-2R^e wherein R^e represents Q. ₄alkyl or phenyl, said Ci^alkyl or phenyl being optionally substituted with 1-3 substituent groups, 1-3 of which are selected from halo and Ci_-3alkyl, and 1-2 of which are selected from the group consisting of: OCi.₃alkyl, haloCi_-3alkyl, haloCi_-3alkoxy, OH, NH₂ and NHQ. ₃alkyl;

b) Ci-6 alkyl and OC|.6alkyl, said group being optionally substituted with 1 -3 groups, 1 -3 of which are halo and 1 -2 of which are selected from: OH, C0₂H,

C0₂C,.₄alkyl, C0₂C haloalkyi, OC0₂C alkyl, NH₂, NHC,. alkyl, N(C alkyl)₂, Hetcy and CN;

c) Hetcy, NHC|.₄alkyl and N(d.₄alkyl)₂, the alkyl portions of which are optionally substituted as set forth in (b) above;

d) C(0)NH₂, C(0)NHC,_-4alkyl, C(0)N(C,. alkyl)₂, C(0)Hetcy, C(0)NHOC alkyl and C(0)N(Ci_-4alkyl)(OCi_-4alkyl), the alkyl portions of which are optionally substituted as set forth in (b) above;

e) NR^'C(0)R", NR SO2R", NR CO2R" and NR^'C(0)NR^"R^"' wherein:

R represents H,

R" represents (a) Ci.₈alkyl optionally substituted with 1 -4 groups, 0-4 of which are halo, and 0-1 of which are selected from the group consisting of: OC,.₆alkyl, OH, C0₂H, C0₂C|.₄alkyl, C0₂C|.₄haloalkyl, OC0₂C alkyl, NH₂, NHC alkyl, N(C alkyl)₂, CN, Hetcy, Aryl and HAR,

said Hetcy, Aryl and HAR being further optionally substituted with 1 -3 halo, C|.₄alkyl, C|.₄alkoxy, haloCi. alkyl and haloC|-₄alkoxy groups;

(b) Hetcy, Aryl or HAR, said Aryl and HAR being further optionally substituted with 1-3 halo, Ci_-4alkyl, Ci_₄alkoxy, haloCi.₄alkyl and haloCj.₄alkoxy groups;

and R" representing H or R"; and

f) phenyl or a 5-6 membered heteroaryl or heterocyclic group attached at any available point and being optionally substituted with 1-3 halo, Ci^alkyl or haloCi- ₃alkyl groups, or 1-2 OCi.₃alkyl or haloOCi^alkyl groups, or 1 moiety selected from the group consisting of:

i) OH; C0₂H; CN; NH₂ ; S(O)₀.₂R^e wherein R^e is as described above; ii) NHCi.₄alkyl and N(C|.₄alkyl)₂, the alkyl portions of which are optionally substituted with 1 -3 groups, 1 -3 of which are halo and 1 -2 of which are selected from: OH, C0₂H, C0₂C|.₄alkyl, C0₂C_Mhaloalkyl, OC0₂C alkyl, NH₂, NHC,.₄alkyl, N(C,. ₄alkyl)₂, CN;

iii) C(0)NH₂, C(0)NHC,.₄alkyl, C(0)N(C,.₄alkyl)₂, C(0)NHOC,. ₄alkyl and C(0)N(Ci.₄alkyl)(OC|.₄alkyl), the alkyl portions of which are optionally substituted as set forth in (b) above; and

iv) NR C(0)R", NR S0₂R", NR C0₂R" and NR^'C(0)NR^"R"' wherein R , R" and R are as described above.

[0037] In some emodiments, a GPR109A agonist is a compound represented by Formula (XXXI):

R, is -CH₂CH₂0-, -C₃H₆-, -C₄H₈-, 1-C3H7, C₃H₇, C4H9, C, ,H₂₃, C₆H₅, 3-C1- Cert,, 4-Cl-C₆H4, 4-CH₃-C₆H4, C₆H₅-CH₂, 4-C1-C6H4-CH2, 4-CH3-C6H4-CH2, 4-OCH₃-C₆H,- CH₂, 3-Cl-C₆H₄-CH₂, C₆H₅-C₂H₄, or C6H5-C3H6; and

R₂ is H.

[0038] In some emodiments, a GPR109A agonist is a compound represented by Formula (XXXVI):

Ri is H, ethyl, n-propyl, w-butyl, e«i-n-butyl, n-pentane, n-hexane, cyclopropyl, cyclopentyl, Ph, 3-Me-Ph, 2-Me-Ph, 4-Cl-Ph, 4-F-Ph, 2,4-F-Ph, 2,5-F-Ph, 2-C1- Ph, 3,4-F-Ph, 2,3-F-Ph, 2-F-Ph, 3-Cl-Ph, 3-F-Ph, 2,3,5-F-Ph, ent 2,3,5-F-Ph, or 3,5-F-Ph, and

R₂ is tetrazole.

[0039) In some emodiments, a GPR109A agonist is a compound represented by Formula (XXXVII):

Ri is H, methyl, ethyl, propyl, /-propyl, c-propyl, butyl, c-butyl, pentyl, and R₂ is H, methyl, or halogen [0040] In some emodiments, a GPR109A agonist is a compound represented by Formula (XXXVIII):

Ri is H, methyl, ethyl, propyl, /-propyl, c-propyl, butyl, and

R₂ is H or halogen

[0041] In some emodiments, a GPR109A agonist is a compound represented by Formula (XXXXIV):

x I

(CR⁶R⁷)_n R⁸

X is selected from the group consisting of: a single bond, O, N(R⁹)C(0),

N(R⁹)C(0)0, OC(0)NR⁹, N(R⁹)C(0)NR¹⁰, NR⁹S0₂, and C(0)NR⁹ if m is 1 , 2, or 3;

Y is selected from the group consisting of: a single bond, and O if n is 1 , 2, 3, 4, 5, or 6;

R¹, R², and R³ are independently from each other selected from the group consisting of: hydrogen, halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, and cycloalkyl;

R⁴, R⁵, R⁶ and R⁷ are independently from each other selected from the group consisting of: hydrogen, fluoro, lower-alkyl, and fluoro-lower-alkyl; or alternatively, R⁴ and R⁵ are bound together to form a ring together with the carbon atom to which they are attached wherein— R— R⁵— is— (CH₂)2-6— , or R⁶ and R⁷ are bound together to form a ring together with the carbon atom to which they are attached wherein— R⁶— R⁷— is— (CH₂)_2-6— ;

R is aryl is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently from each other selected from the group consisting of: halogen, lower-alkyl, lower-alkoxy, fluoro-lower-alkyl, fluoro-lower-alkoxy, cycloalkyl, fluoro-cycloalkyl, cycloalkyl-oxy, C(0)OH, lower-alkoxy-C(O), NH₂C(0), N(H,lower-alkyl)C(0), N(lower-alkyl)₂C(0), OH, lower-alky l-C(0)0, NH₂, N(H,lower- alkyl), N(lower-alkyl)₂, lower-alkyl-C(0)NH, lower-alkyl-C(0)N(lower-alkyl), NH₂S0₂, N(H,lower-alkyl)S0₂, N(lower-alkyl)₂S0₂, lower-alky 1-S02— NH, lower-alkyl-SO;.— N(lower-alkyl), cyano, and phenyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, lower-alkyl, lower-alkoxy and fluoro-lower-alkyl;

R⁹ and R¹⁰ independently from each other are selected from the group consisting of: hydrogen, lower-alkyl, and fluoro-lower-alkyl; and

m is 0, 1 , 2 or 3; and n is 0, 1, 2, 3, 4, 5 or 6; wherein m+n is >1.

[0042] In some emodiments, a GPR109A agonist is a compound represented by Formula (XXXXV):

R¹ represents hydrogen, halogen or Ci-C3alkyl;

R² represents a 6 or 10-member aryl or heteroaryl ring system;

W represents a linker selected from:— C(R³R⁴)— (CH₂)„— ,— C(R³R⁴)—

(CH₂)„NHC(0)— ,— C(R³R⁴)— (CH₂)„NHC(0)NH— ,— C(R³R⁴)— (CH₂)„NHC(0)0— , C(R³R⁴)— (CH₂)„S0₂NR5³— ,— C(R³R⁴>— (CH₂)„NR⁵S0₂— ,— C(R³R⁴)— (CH₂)„0— ,

> 3r> 4

C(R³R⁴)— (CH₂)„C(0>— ,— C(R^JR'^t)— (CH₂)„NH— ,— C(R^JR"— (CH₂)„S— ,— C(R > ^J3Rr> 4.

V represents CH or N;

X, Y and Z independently represent CH, O, N or S, with the proviso that all three of X, Y and Z may not represent CH;

A represents a linker selected from:— C(R³R⁴>— (CH₂)„— ,— C(R³R >— (CH₂)_nO—

,— C(R³R⁴)— (CH₂)„NH— , or— C(R³R⁴)— {CH₂)„S— ;

n represents an integer selected from 0, 1 and 2;

R³ represents hydrogen, Ci-Csalkyl, C₂-Csalkenyl, Cs-Cearyl or Cs-C₆cycloalkyl; R⁴ represents, C]-C₅alkyl, C₂-C₅alkenyl, C₅-C₆aryl or C₅-C₆cycloalkyl or R³ and R⁴ together with the carbon atom to which they are attached form a 4, 5, 6 or 7-member cycloalkyl ring; and

R⁵ represents hydrogen or C|-C₃alkyl.

[0043] Some embodiments of the present invention are set forth in claim format directly below:

1. A method for the treatment or alleviation of an ischemic condition in a subject, the method comprising the steps of:

(a) selecting a subject having an ischemic condition; and

(b) administering to said subject a therapeutically effective amount of a G- protein coupled receptor 109A (GPR109A) agonist or a pharmaceutically acceptable salt or solvate thereof

wherein said ischemic condition is treated or alleviated.

2. The method according to claim 1 , wherein the ischemic condition results .

from coronary artery bypass graft surgery, cerebral ischemia, focal cerebral infarction, cerebral hemorrhage, hemorrhage infarction, hypertensive hemorrhage, intracranial vascular hemorrhage, subarachnoid hemorrhage, hypertensive encephalopathy, carotid stenosis or occlusion, cardiogenic thromboembolism, spinal stroke, spinal cord injury, atherosclerosis, vasculitis, macular degeneration, myocardial infarction, cardiac ischemia or supraventricular tachyarrhythmia.

3. The method according to any one of claims 1 to 2, wherein the ischemic condition is cerebral ischemia. 4. The method according to any one of claims 1 to 3, wherein the GPR109A agonist is a compound represented by Formula (I):

5. The method according to any one of claims 1 to 3, wherein the GPR109A agonist a compound represented by Formula (II):

6. The method according to any one of claims 1 to 3, wherein the GPR109A agonist a compound represented by Formula (III):

7. The method according to any one of claims 1 to 3, wherein the GPR109A agonist is a compound represented by Formula (IV):

wherein R is

8. The method according to any one of claims 1 -3, wherein the GPR109A agonist is a compound represented by Formula (V):

wherein R is

9. The method according to any one of claims 1 -3, wherein the GPR109A agonist is a compound represented by Formula (VI):

10. The method according to any one of claims 1 to 3, wherein the GPR109A agonist is a compound represented by Formula (VII):

1 1. The method according to any one of claims 1 -3, wherein the GPR 109A agonist is a compound represented by Formula (VIII):

12. The method according to any one of claims 1 to 3, wherein the GPR109A agonist is a compound represented by Formula (IX):

13. The method according to any one of claims 1 to 3, wherein the GPR109A agonist is a compound represented by Formula (X):

14. The method according to any opne of claims 1 to 3, wherein the GPR109 A agonist is a compound represented by Formula (XI):

15. The method according to any one of claims 1 to 3, wherein the GPR109 A agonist is a compound represented by Formula (XII):

16. The method according to any one of claims 1 to 3, wherein the GPR109A agonist is a compound represented by Formula (XIII):

Ri is Ph, vinyl, Ethyl, 1-spiro, spirocyc, 1 -cyclopentenyl, 1-cyclohexenyl, 3- pyrimidine. 4-pyrimidine, 2-furan, 2,5-diCl-Ph, 2,4-diF-Ph, 3,4-diF-Ph, 2,6-diF-Ph, 3,5-diF Ph, 2-F-Ph, 4-F-Ph. 3-F-Ph, 3-Cl-Ph, 3-Br-Ph, 3-I-Ph, 3-Me-Ph, 3-Et-Ph, 3-CF3-Ph, or 3- OMe-Ph; and

R₂ is Me, Et, indane, or lopetane.

17. The method according to any one of claims 1 to 3, wherein the GPR109 A agonist a compound represented by Formula (XIV):

Ri is 2-thienyl, 5-Cl-2-thienyl, 5-Me-2-thienyl, 4-Br-2-thienyl, 4-Me-2- thienyl, 4-Br-5-Me-2-thienyl, 3-thienyl, 5-Cl-3-thienyl, 5-Br-3-thienyl, or 5 -Me-3 -thienyl. 18. The method according to any one of claims 1 to 3, wherein the GPR109 A agonist is a compound represented by Formula (XXI):

X represents a nitrogen or carbon atom;

R⁶ represents Ci_3alkyl optionally substituted with 1 -3 halo groups;

the dashed lines represent optional bonds;

when the dashed line to Z represents a bond that is absent, the dashed line to (Y)_p represents a bond that is present and Z represents a group selected from OH, SH, NH₂, C0₂H and S0₃H;

each R⁴ is H or halo, or is selected from the group consisting of:

a) a phenyl or a 5-6 membered heteroaryl group containing 1 heteroatom selected from O, S and N, and optionally containing 1-3 additional N atoms, said phenyl and heteroaryl groups being optionally substituted with 1-3 substituents, 1-3 of which are halo, and 0- 1 of which are selected from: OH, NH₂, Ci.3alk.yl, Ci.₃alkoxy, haloCi^alkyl and haloC].3alkoxy; and (b) Ci alkyl optionally substituted with 1 -3 substituent groups, 1 -3 of which are halo atoms, and 0-1 of which are selected from the group consisting of: OH, OCi. ₃alkyl, NH₂, NHCi-₃alkyl, N(Ci.₃alkyl)₂, CN, N0₂, Hetcy, phenyl and a 5-6 membered heteroaryl group containing 1 heteroatom selected from O, S and N, and optionally containing 1 -3 additional N atoms, said phenyl and heteroaryl groups being optionally substituted with 1 -3 substituents, 1 -3 of which are halo, and 0- 1 of which are selected from: OH, NH₂, Ci alkyl, Ci_-3alkoxy, haloCi_₃alkyl and haloQoalkoxy;

ring A represents a 6-10 membered aryl, a 5-13 membered heteroaryl or a partially aromatic heterocyclic group, said heteroaryl and partially aromatic heterocyclic group containing at least one heteroatom selected from O, S and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1-3 additional N atoms, with up to 5 heteroatoms being present;

R² and R³ are independently H, Cioalkyl, haloCioalkyl, OQoalkyl, haloCi. ₃alkoxy, OH, NH₂ or F;

n represents an integer of from 1 to 5;

each R¹ is H or is selected from the group consisting of:

a) halo, OH, C0₂H, CN, NH₂, S(O)₀.₂R^e wherein R^e represents C,. ₄alkyl or phenyl, said C^alkyl or phenyl being optionally substituted with 1 -3 substituent groups, 1 -3 of which are selected from halo and Cioalkyl, and 1 -2 of which are selected from the group consisting of: OCioalkyl, haloCioalkyl, haloQoalkoxy, OH, NH₂ and NHC|. ₃alkyl;

b) Ci-6 alkyl and OCi_₆alkyl, said group being optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, C0₂H, C0₂C alkyl, C0₂C haloalkyl, OCO^ alkyl, NH₂, NHC alkyl, N(C alkyl)₂, Hetcy and CN;

c) Hetcy, NHCMalkyl and N(Ci-₄alkyl)₂, the alkyl portions of which are optionally substituted as set forth in (b) above;

d) C(0)NH₂, C(0)NHC alkyl, C(0)N(C alkyl)₂, C(0)Hetcy, C(0)NHOC alkyl and C(0)N(Ci.₄alkyl)(OC|.₄alkyl), the alkyl portions of which are optionally substituted as set forth in (b) above;

e) NR C(0)R", NR S0₂R", NR C0₂R" and NR C(0)NR R wherein:

R represents H, C|.₃alkyl or haloCioalkyl,

R" represents (a) Ci.salkyl optionally substituted with 1 -4 groups, 0-4 of which are halo, and 0-1 of which are selected from the group consisting of: OC,.₆alkyl, OH, C0₂H, C0₂C alkyl, C0₂Ci_-4haloalkyl, OC0₂C alkyl, NH₂, NHC|_-4alkyl, N(C_Malkyl)₂, CN, Hetcy, Aryl and HAR,

said Hetcy, Aryl and HAR being further optionally substituted with 1-3 halo, Ci^alkyl, C|.₄alkoxy, haloCi_-4alkyl and haloCi.₄alkoxy groups;

(b) Hetcy, Aryl or HAR, said Aryl and HAR being further optionally substituted with 1 -3 halo, C|.₄alkyl, Ci.₄alkoxy, haloC|.₄alkyl and haloCi_₄alkoxy groups;

and R'" representing H or R"; and

f) phenyl or a 5-6 membered heteroaryl or heterocyclic group attached at any available point and being optionally substituted with 1 -3 halo,

or haloCi. ₃alkyl groups, or 1 -2 OCi alkyl or haloOCi alkyl groups, or 1 moiety selected from the group consisting of:

i) OH; C0₂H; CN; NH₂ ; S(O)_0-2R^e wherein R^e is as described above; ii) NHCi_-4alkyl and N(Ci_-4alkyl)₂, the alkyl portions of which are optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, C0₂H, C0₂C alkyl, C0₂C_)-4haloalkyl, OC0₂C alkyl, NH₂, NHC_1-4alkyl, N(Ci- ₄alkyl)₂, CN;

iii) C(0)NH₂, CCOiNHC alkyl, C(0)N(C,. alkyl)₂, C(0)NHOCi. ₄alkyl and C(0)N(C|. alkyl)(OC alkyl), the alkyl portions of which are optionally substituted as set forth in (b) above; and

iv) NR C(0)R", NR S0₂R", NR C0₂R" and NR^'C(0)NR^"R'" wherein

R , R" and R are as described above.

19. The method according to any one of claims 1 to 3, wherein the GPR109A agonist is a compound represented by Formula (XXXI):

R, is -CH₂CH₂0-, -C3H6-, -C₄H₈-, -C3H7, C3H7, C4H9, C_nH₂₃, C₆H₅, 3-Cl-C₆H , 4-Cl-C₆H₄, 4-CH3-C6R1, C₆H₅-CH₂, 4-Cl-C₆H₄-CH₂, 4-CH3-C₆H4-CH₂, 4- OCH₃-C₆H4-CH₂, 3-Cl-C₆H₄-CH₂₎ CeHs^Hi, or C₆H5-C₃H₆; and

R₂ is H. 20. The method according to any one of claims 1 to 3, wherein the GPR109A agonist is a compound represented by Formula (XXXVI):

Ri is H, ethyl, ^-propyl, «-butyl, e«i-n-butyl, w-pentane, w-hexane, cyclopropyl, cyclopentyl, Ph, 3-Me-Ph, 2-Me-Ph, 4-Cl-Ph, 4-F-Ph, 2,4-F-Ph, 2,5-F-Ph, 2-CI- Ph, 3,4-F-Ph, 2,3-F-Ph, 2-F-Ph, 3-Cl-Ph, 3-F-Ph, 2,3,5-F-Ph, ent 2,3,5-F-Ph, or 3,5-F-Ph, and

R₂ is tetrazole.

21 . The method according to any one of claims 1 to 3, wherein the GPR1 09A agonist is a compound represented by Formula (XXXVII):

Ri is H, methyl, ethyl, propyl, /-propyl, c-propyl, butyl, c-butyl, pentyl, and R₂ is H, methyl, or halogen.

22. The method according to any one of claims 1 to 3, wherein the GPR109A agonist is a compound represented by Formula (XXXVIII):

Ri is H, methyl, ethyl, propyl, /-propyl, c-propyl, butyl, and

R₂ is H or halogen. 23. The method according to any one of claims 1 to 3, wherein the GPR109A agonist a compound represented by Formula (XXXXIV):

X

(CR⁶R⁷)_n

R⁸

X is selected from the group consisting of: a single bond, O, N(R )C(0), C(0)NR⁹, N(R⁹)C(0)NR¹⁰, NR⁹S0₂, and C(0)NR⁹ if m is 1 , 2, or 3;

Y is selected from the group consisting of: a single bond, and O if n is 1 , 2, 3,

4, 5, or 6;

, and R are independently from each other selected from the group consisting of: hydrogen, halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, fluoro- lower-alkoxy, and cycloalkyl;

R⁴, R⁵, R⁶ and R⁷ are independently from each other selected from the group consisting of: hydrogen, fluoro, lower-alkyl, and fluoro-lower-alkyl; or alternatively, R⁴ and R⁵ are bound together to form a ring together with the carbon atom to which they are attached wherein— R— R⁵— is— (CH₂)₂.6— , or R⁶ and R⁷ are bound together to form a ring together with the carbon atom to which they are attached wherein— R⁶— R⁷— is— (CH₂)_2-6— ;

R is aryl is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently from each other selected from the group consisting of: halogen, lower-alkyl, lower-alkoxy, fluoro-lower-alkyl, fluoro-lower-alkoxy, cycloalkyl, fluoro-cycloalkyl, cycloalkyl-oxy, C(0)OH, lower-alkoxy-C(O), NH₂C(0), N(H,lower-alkyl)C(0), N(lower-alkyl)₂C(0), OH, lower-alkyl-C(0)0, NH₂, N(H,lower- alkyl), N(lower-alkyl)₂, lower-alkyl-C(0)NH, lower-alkyl-C(0)N(lower-alkyl), H₂S0₂, N(H,lower-alkyl)S0₂, N(lower-alkyl)₂S0₂, lower-alky l-S0₂— NH, lower-alkyl-SC>2—

N(lower-alkyl), cyano, and phenyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, lower-alkyl, lower-alkoxy and fluoro-lower-alkyl;

m is 0, 1 , 2 or 3; and n is 0, 1, 2, 3, 4, 5 or 6; wherein m+n is >1.

24. The method according to any one of claims 1 to 3, wherein the GPR109A agonist is a compound represented by Formula (XXXXV):

R¹ represents hydrogen, halogen or Ci-C₃alkyl;

R² represents a 6 or 10-member aryl or heteroaryl ring system;

(CH₂)„NHC(0)— ,— C(R³R⁴)— (CH₂)„NHC(0)NH— ,— C(R³R⁴)— (CH₂)_nNHC(0)0— , C(R³R⁴)— (CH₂)„S0₂NR5³— ,— C(R³R⁴)— (CH₂)„NR⁵S0₂— ,— C(R³R⁴)— (CH₂)_nO— , 3R⁴)— (CH₂)„C ³R⁴)— (CH₂)„NH— ,— C(R³R⁴)— (CH₂)„S—— C(R³R⁴

V represents CH or N;

A represents a linker selected from:— C(R³R⁴)— (CH₂)„— ,— C(R³R⁴)— (CH₂)„0— ,— C(R³R⁴)— (CH₂)„NH— , or— C(R³R⁴)— (CH₂)„S— ;

n represents an integer selected from 0, 1 and 2;

R³ represents hydrogen, Ci-Csalkyl, C₂-C₅alkenyl, Cs-Cearyl or C₅-C₆cycloalkyl; R⁴ represents, Ci-C₅alkyl, C₂-Csalkenyl, Cs-Cearyl or Cs-Cecycloalkyl or R³ and R⁴ together with the carbon atom to which they are attached form a 4, 5, 6 or 7-member cycloalkyl ring; and

R⁵ represents hydrogen or Ci-C₃alkyl.

25. The method according to any one of claims 1 to 24, further comprising the step of:

(c) administering to said subject

(i) an agent having neurotrophic activity selected from the group consisting of NGF, BFNF, ADNF, and GDNF; or

(ii) a compound that enhances the neurotrophic activity of (i).

26. The method according to any one of claims 1 to 24, further comprising the step of:

(c) administering to said subject

(i) a lipid modifying compound; or

(ii) an active agent.

27. A method for treating a subject having a high risk for a stroke, the method comprising the steps of:

(a) selecting a subject having a high risk for a stroke; and

(b) administering to said subject a therapeutically effective amount of a G- protein coupled receptor 109A (GPR109A) agonist or a pharmaceutically acceptable salt or solvate thereof.

28. The method according to claim 27, wherein the GPR109 A agonist is a GPR109A agonist as in any one of claims 4 to 24.

29. The method according to any one of claims 27 to 28, wherein the subject has experienced a prior ischemic event.

30. The method according to any one of claims 27 to 29, wherein the subject has one or more risk factor selected from the group consisting of arterial hypertension,

hypercholesterolemia, diabetes, smoking, auricular fibrillation, an embolic heart disease, and increasing age.

31. A method for decreasing the severity of an infarct in a subject afflicted with a cerebral ischemia, the method comprising the steps of:

(a) selecting a subject having a cerebral ischemia;

(b) determining the severity of an infarct; and

(c) administering to said subject a therapeutically effective amount of a G- protein coupled receptor 109A (GPR109A) agonist or a pharmaceutically acceptable salt or solvate thereof,

wherein said severity of the infarct is decreased.

32. The method according to claim 31 , wherein the GPR109A agonist is a GPR109A agonist as in any one of claims 4 to 24.

33. Use of a GPR109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof as in any one of claims 4 to 24 in the manufacture of a medicament for the treatment or alleviation of an ischemic condition.

34. Use of a GPR109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof as in any one of claims 4 to 24 in the manufacture of a medicament for the treatment of a subject having a high risk for a stroke.

35. Use of a GPR109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof as in any one of claims 4 to 24 in the manufacture of a medicament for decreasing the severity of an infarct in a subject afflicted with cerebral ischemia.

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 A schematically depicts the GPR 109A receptor, signal transduction and its localization on cells. GPR109A is found on peripheral immune cells, such as macrophages and neutrophils. In addition, it is localized on adipocytes. Both GPR109A and the related receptor CB2, signal through Gi proteins.

[0045] Figure I B schematically depicts a mode of action of nicotinic acid. By activating GPR109A receptors in adipocytes, nicotinic acid blocks the hormone sensitive lipase (HSL) that produces free fatty acids (FAA) in adipocytes. For details, see, Gille and Offermanns, 2008, Annu Rev Pharmacol Toxicol 48:79:79-106.

[0046] Figure 2 depicts that the GPR109A agonist nicotinic acid reduced the infarct volume in a mouse model of stroke. Nicotinic acid was administered by ip injection before onset of ischemia, 4 hours, 8 hours, 24 hours, 28 hours, and 32 hours after onset. In this experiment, the lowest effect dose was 50 mg kg. (a) Nicotinic acid in a dose of 200 mg/kg reduced the infarct size in comparison to a vehicle-treated group*, p<0.02 (t-test, n= 12- 14). (b) Nicotinic acid in a dose of 150 mg/kg (n=10) and 100 mg/kg (n=10) reduced the infarct size significantly (by almost 50%) in comparison to a vehicle-treated group (n=10). ANOVA (analysis of variance), F(2/27) (degrees of freedom between groups/degrees of freedom of residual) = 9.262, p<0.00l. *, p<0.005 compared to vehicle-treated group (Student-Newman- euls Method), (c) Nicotninic acid in a dose of 200 mg/kg (n=9) or 50 mg/kg (n=9) reduced the infarct size significantly in comparison to a vehicle-treated group (n=7). ANOVA, F(2/18) = 5.469, p<0.02. *, p<0.05 compared to vehicle-treated group (Student-Newman- euls Method). Further details are described in Example 2.

[00471 Figure 3 depicts pyrazole GPR109A agonists described in WO2008/051403 (incorporated by reference in its entirety).

[0048| Figure 4 depicts structure and structure-activity relationship (SAR) of 6-membered heterocyclic acid GPR109A agonists (A), 5-membered heterocyclic acid GPR109A agonists (B), 5-substituted pyrazole acid GPR109A agonists (C) and bicyclic pyrazole acid GPR109A agonists for use in the methods of the present invention. N.e., less than 50% activity observed at any concentration up to 30 uM in the cAMP assay used. Values are means of multiple determinations. The number of experiments is listed in parentheses. The standard deviations where calculable were <30% of the mean. Details of synthesis and in vitro SAR a of the compounds in (A), (B), (C), and (D) are described in Gharbaoui et al. , 2007, Biooorg Med Chem Lett 17:4914-4919; incorporated by reference in its entirety.

[0049] Figure 5 depicts structure-activity relationship (SAR) of pyrazolopyrimidine GPR109 agonists for use in the methods of the present invention. Values were means of at least three experiments; average standard deviation is about 20%; na, not active in assay used. Details of synthesis and in vitro SAR a of pyrazolopyrimidine analogs are described in Shen et al., 2008, Bioorg Med Chem Lett 18:4948-4951 ; incorporated by reference in its entirety.

[0050[ Figure 6 depicts structure-activity relationship (SAR) of [6,6,5] tricyclic

anthranilide GPR109A agonists for use in the methods of the present invention. Values are based on one or two experiments, each in triplicate, and within 20% deviation upon repeat; b, ratio of compound binding ICso in the presence and absence of 4% human serum; c, hyphens indicate that compounds were not tested. Details of synthesis and in vitro SAR of [6,6,5] tricyclic anthranilide analogs are described in Shen et al., 2009, J Med Chem 52:2587-2602; incorporated by reference in its entirety.

[0051] Figure 7 depicts structure-activity relationship (SAR) of [6,5,5], [6,6,6], [5,6,6] tricyclic and naphthol antranilide GPR109A agonists for use in the methods of the present invention. Values are based on one or two experiments, each in triplicate, and within 20% deviation upon repeat; b, ratio of compound binding IC50 in the presence and absence of 4% human serum; c, hyphens indicate that compounds were not tested. Details of synthesis and in vitro SAR a of [6,5,5], [6,6,6], [5,6,6] tricyclic and naphthol antranilide analogs are described in Shen et al., 2009, J Med Che m 52:2587-2602; incorporated by reference in its entirety.

[0052] Figure 8 depicts structure and structure-activity relationship (SAR) of biaryl anthranilide GPR109A agonists for use in the methods of the present invention. Details of synthesis and in vitro SAR a of biaryl anthranilide analogs (compounds la through Id and compounds 2a through 2j) are described in Shen et al, 2007, J Med Chem 50:6303-6306; incorporated by reference in its entirety.

[0053] Figure 9 depicts structure and structure-activity relationship (SAR) of biheteroaryl anthranilide GPR109A agonists for use in the methods of the present invention. Details of synthesis and in vitro SAR a of biheteroaryl anthranilide analogs (compounds 2k through 2o) are described in Shen et al. , 2007, J Med Chem 50:6303-6306; incorporated by reference in its entirety.

[0054] Figure 10 depicts structure-activity relationship (SAR) of tricyclic cycloalkene carboxylic acid GPR109A agonists for use in the methods of the present invention. On average, repeat determination differed by ± 20%; b, ratio of compound binding IC50 in the presence and absence of 4% human serum; c, hyphens indicate that compounds were not tested; d, in this experiment, the niacin control has IC50 of 0.44μΜ. The IC50 of compound 3e was adjusted accordingly. Details of synthesis and in vitro SAR a of tricyclic cycloalkene carboxylic acid analogs (compounds 3a through 3h) are described in Shen et al, 2009, J Med Chem 52:2587-2602; incorporated by reference in its entirety.

[0055] Figure 1 1 depicts structure-activity relationship (SAR) of urea GPR109 A agonists for use in the methods of the present invention. Values are based on one or two experiments, each in triplicate, and within 20% deviation upon repetition. Missing data were due to inconclusive reading as a result of the curve shape in the assay used. Details of synthesis and in vitro SAR a of urea analogs (compounds l a through l x) are described in Shen et al, 2007, Bioorg Med Chem Lett 1 7:6723-6728; incorporated by reference in its entirety.

[0056] Figure 12 depicts structures of GPR109A agonists.

[0057] Figure 13 depicts imaging of GPR109A⁺ cells in the ischemic brain. A BAC reporter mouse expressing red fluorescent protein (RFP) under control of the GPR109A locus enables the visualization of GPR109A⁺ cells in the ischemic brain by 2P.

Immunohistochemistry showed that in these mice, RFP is expressed in CD1 l b⁺ microglia, but not in GFAP⁺ astrocytes or NeuN* neurons. DETAILED DESCRIPTION OF THE INVENTION I. DEFINITIONS

[0058] All methods described herein can be performed in any suitable order and combination unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0059] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Unless otherwise indicated, nucleic acids are written left to right in 5' to 3' orientation; amino acid sequences are written left to right in amino to carboxy orientation.

[0060] It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes mixtures of compounds, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

[0061] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated- range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0062] The headings used herein are for organizational purposes only and are not meant to be used to limit the scope of the description or the claims, which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0063] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et ai, Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0064] As used herein, the terms "administering," "administration" or grammatical equivalents thereof refer to the actual physical introduction of a composition into or onto (as appropriate) a host or subject. Any and all methods of introducing the composition into or onto a host or subject are contemplated according to the invention. Methods of the present invention are not dependent on any particular means of introduction and are not to be so construed. Means of introduction are well-known to those skilled in the art, and also are exemplified herein.

[0065] As used herein, the term "administration in combination" refers to both

simultaneous and sequential administration of at least two compounds. Specifically, a GPR109A agonist as described herein can be delivered or administered with another agent or composition at the same site or a different site and can be administered at the same time or after a delay not exceeding 48 hours. Concurrent or combined administration, as used herein, means that a GPR109A agonist as described herein and a second compound or composition are administered to the subject either (a) simultaneously, or (b) at different times during the course of a common treatment schedule. In the latter case, the two compounds are administered sufficiently close in time to achieve the intended effect.

[0066] As used herein, the term "agonist" refers to a compound which will elicit a response similar to a natural ligand, especially in terms of cell signaling and responses. More specifically, as used herein, the term "GPR109A agonist" refers to a compound that activates a high-affinity nicotinic receptor, G-coupled receptor 109A (GPR109A) polypeptide.

GPR109A agonists, e.g., bind to, stimulate, increase, activate, facilitate, or enhance activation, sensitize or up regulate the activity of a GPR109A polypeptide. GPR109A agonists include naturally occurring and synthetic compounds, small chemical molecules and the like. Assays for GPR109A agonists include, e.g., applying a GPR109A agonist or candidate GPR109A agonist to a cell expressing a GPR109A polynucleotide and/or a GPR109A polypeptide and then determining the functional effect(s) of such agent. Samples or assays comprising a GPR109A polynucleotide and/or a GPR109A polypeptide that are treated with a candidate GPR109A agonist are compared to control samples without the agonist to examine the extent of effect. Control samples (untreated with a GPRl 09 A agonist) are assigned a relative activity value of 100%. Activation of a GPR109A polynucleotide and/or an GPR109A polypeptide is achieved when the GPR109A polynucleotide and/or the GPR109A polypeptide activity value relative to the control is 1 10%, 120%, 130%, 140%, 150%, 200%, 300%, 400%, 500%, or 1000-3000% or more higher. GPR109A polypeptide activity can be monitored, for example, by the ability to activate downstream signaling components such as heterotrimeric G-proteins, phospholipase C activity, protein kinase C

2+

activity, and increases in the free intracellular Ca concentration.

[0067] As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon radical, and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. Ci-C₆ means one to six carbons). The branched or straight-chain monovalent saturated aliphatic hydrocarbon radical may consist of one to twenty carbon atoms. In some embodiments, the alkyl is one to sixteen carbon atoms, in other embodiments, one to ten carbon atoms. In yet other embodiments, the alkyl is a lower-alkyl. The term "lower-alkyl," alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to seven carbon atoms. In some embodiments, the lower alkyl has one to four carbon atoms. Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0068] As used herein, the term "alkenyl" refers to an unsaturated alkyl group one having one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl and 3-(l,4-pentadienyl), and the higher homologs and isomers.

[0069] As used herein, the term "alkoxy" refers to -OR^ wherein is alkyl as defined herein. The term "lower-alkoxy" refers to OR^ wherein R^ is a lower alkyl as defined herein. Representative examples of alkoxy groups include methoxy, ethoxy, i-butoxy, trifluoromethoxy, and the like.

[0070] As used herein, the term "alkynyl" refers to an unsaturated alkyl group one having one or more triple bonds. Examples of alkynyl groups include ethynyl (acetylenyl), 1 - propynyl, 1 - and 2-butynyl, and the higher homologs and isomers.

[0071] As used herein, the term "amount effective" or "amount sufficient" means an amount which produces the desired effect. An "amount sufficient" or "amount effective" is that amount of a given composition that exhibits the activity of interest or, which provides either a subjective relief of a symptom(s) or an objectively identifiable improvement as noted by a clinician or other qualified observer. The dosing range varies with the composition used, the route of administration and the potency of the particular composition. [0072] As used herein, the term "aryl" (or "Ar") refers to an aromatic hydrocarbon having 5-12 carbon ring members, which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Non-limiting examples of aryl groups include phenyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, and benzyl. Other aryl groups are also useful in the present invention, including heteroaryl groups in which the heteroatom may be nitrogen.

[0073] As used herein, the term "biaryl" (when used as a group or as part of a group) refers to a group containing the specified number of atoms and containing two aromatic rings which have two atoms in common. Examples of biaryl as used herein include, but are not limited to naphthyl. Said biaryl groups may be optionally substituted, In some embodiments of the present invention, the substitutions may be one or more groups selected from Ci-C3alkyl, Ci- C₃alkoxy,— C(0)Me, C0₂H, C0₂Me and =0.

[0074] As used herein, the term "biological sample" refers to a sample of biological tissue or fluid that contains nucleic acids and/or polypeptides. Such samples are typically from humans, but include tissues isolated from non-human primates, or rodents, e.g., mice, and rats. Biological samples may also include sections of tissues such as tissue biopsy and autopsy samples, frozen sections taken for histological purposes, e.g., brain tissue. Fluid samples include blood, plasma, serum, lymph, sputum, stool, tears, mucus, hair, skin, buccal scrape, nipple discharge, etc. Biological samples also include explants and primary and/or transformed cell cultures derived from patient tissues, e.g., cells derived from brain tissue. A "biological sample" also refers to a cell or population of cells or a quantity of tissue or fluid from an animal. Most often, the biological sample has been removed from an animal, but the term "biological sample" can also refer to cells or tissue analyzed in vivo, i.e., without removal from the animal. Typically, a "biological sample" will contain cells from the animal, but the term can also refer to noncellular biological material, such as noncellular fractions of blood, saliva, or urine, that can be used to measure polynucleotide or polypeptide levels. As used herein, a "tissue biopsy" refers to an amount of tissue removed from an animal, preferably a human, for diagnostic analysis. In a patient afflicted with an ischemic condition, tissue may be removed from the brain of the patient, allowing the analysis of cells within the brain. "Tissue biopsy" can refer to any type of biopsy, such as needle biopsy, fine needle biopsy, surgical biopsy, etc.

[0075] "Providing a biological sample" or "obtaining a biological sample" means to obtain a biological sample for use in methods or compositions of the present invention. Most often, this will be done by removing a sample of cells from a subject, e.g., patient, but can also be accomplished by using previously isolated cells (e.g., isolated by another person, at another time, and/or for another purpose), or by performing the methods of the invention in vivo. Archival tissues, having treatment or outcome history, will be particularly useful.

[0076] In each of the embodiments designating a number of atoms e.g. "Ci _8" is meant to include all possible embodiments that have one fewer atom. Non-limiting examples include C\ . , C2-8, C2-7, C3.8, C3.7 and the like.

[0077] As used herein, the term "carrier" in the context of "pharmaceutically acceptable carrier" refers to an inert substance used as a diluent, adjuvant, excipient or vehicle with which a drug, medicament or vaccine is administered.

[0078] As used herein, the term "contacting" refers to an instance of exposure of at least one substance to another substance and includes reference to placement of at least one substance to another substance in direct physical association. For example, contacting can include contacting a substance, such as a GPR109A agonist to a GPR109A polypeptide described herein. A GPR109A agonist can be contacted with the GPR109A polypeptide, for example, by adding the GPR109A agonist to a cell expressing the GPR109A polypeptide or by adding a GPR109A agonist to the extracellular fluid in vivo (by local delivery, systemic delivery, intravenous injection, bolus delivery, or continuous infusion). The duration of contact with a cell or group of cells is determined by the time a GPR109A agonist is present at a physiologically effective level or at presumed physiologically effective levels in the medium or extracellular fluid bathing the cell. The term "contacting" is used herein interchangeably with the following: combined with, added to; mixed with, passed over, incubated with, flowed over, etc.

[0079] As used herein, the term "cycloalkyl" refers to a subset of alkyl. If no number of atoms is specified, 3-7 carbon atoms are intended, forming 1 -3 carbocyclic rings that are fused. "Cycloalkyl" also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.

[0080] As used herein, the term "determining the functional effect" refers to assaying for a compound that increases (e.g., an agonist) or decreases (e.g., an antagonist) a parameter that is indirectly or directly under the influence of a GPR109 A receptor, e.g., functional, enzymatic, physical and chemical effects. Such functional effects can be measured by any means known to those skilled in the art, e.g., changes in spectroscopic characteristics (e.g., fluorescence, absorbance, refractive index), hydrodynamic (e.g., shape), chromatographic, or solubility properties for the protein, measuring inducible markers or transcriptional activation of the GPR109A receptor protein or of transcriptional activation of a gene under control by a GPR109A receptor; measuring binding activity, e.g., binding to a GPR109A receptor, measuring cellular proliferation, measuring apoptosis, measuring the activity of

heterotrymeric G-protein whjch is under the control of GPR109A, determining the activity of downstream signaling molecules such as phospholipase C, protein kinase C, adenylyl cyclase or NAP kinases, measuring changes in the free intracellular Ca²⁺ concentration, measuring of lipid profiles in vivo, measuring of lipolytic activity in cells, or the like. Determination of the functional effect of a compound on an ischemic condition, such as cerebral ischemia, can also be performed using assays known to those of skill in the art such as in vitro and in vivo assays, e.g., cell death studies after oxygen and glucose deprivation; investigation of the infarct size and neurological deficit in animal models of stroke; quantification of the number of inflammatory cells in the brain; quantification of brain edema; quantification of biomarkers (e.g., S I 00, GFAP, HMGB 1 , and others known in the art) released from the brain into the blood; quantification of apoptotic cell death in the ischemic brain; mRNA and protein expression in cells affected by cerebral ischemia. The functional effects can be evaluated by many means known to those skilled in the art, e.g., microscopy for quantitative or qualitative measures of alterations in morpho logical features, measurement of changes in GPR109A receptor RNA or protein levels, measurement of RNA stability, identification of downstream or reporter gene expression (CAT, luciferase, β-gal, GFP and the like), e.g., via

chemiluminescence, fluorescence, colorimetric reactions, antibody binding, inducible markers, and ligand binding assays. "Functional effects" include in vitro, in vivo, and ex vivo activities.

[0081) As used herein, the term "fluoro-cycloalkyl" refers to a cycloalkyl group as defined above, which is mono- or multiply substituted with fluorine (preferably with 1 to 4 fluorine atoms). Non-limiting examples of fluoro-cycloalkyl are 2-fluorocyclopropyl, 2,2- difluorocyclopropyl, 2,2,3, 3-tetrafluorocyclopropyl, 3-fluorocyclobutyl, 3,3- difluorocyclobutyl, and 3,3-difluorocyclopentyl.

[0082] As used herein, the term "fluoro-lower-alkyl" refers to lower-alkyl groups which are mono- or multiply substituted with fluorine. Examples of fluoro-lower-alkyl groups are e.g. CFH₂, CF₂H, CF₃, CF3CH2, CF₃(CH₂)₂, (CF₃)₂CH and CF₂H— CF₂. [0083] The term "fluoro-lower-alkoxy" refers to OR^ wherein is fluoro-lower-alkyl. Examples of fluoro-lower-alkoxy groups are CFH₂— O, CF₂H— O, CF₃— O, CF₃CH₂— O, CF₃(CH₂)₂— O, (CF₃)₂CH— O, and CF₂H— CF₂— O.

[0084] As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Exemplary, non-limiting, haloalkyl groups include CF₃, CC1₃, CHF₂, CHC1₂, C₂F₅,C₂Cl₅,and the like.

[0085] As used herein, the term "halogen" refers to the elements including fluorine (F), chlorine (CI), bromine (Br) and iodine (I).

[0086] As used herein, the term "heteroaryl" (HAR)refers to a cyclic or polycyclic aromatic radical that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom or through a carbon atom and can contain 5 to 10 carbon atoms. Non-limiting examples of heteroaryl groups include 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1 -pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,

3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl and 4-pyrimidyl. If not specifically stated, substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described herein. "Substituted heteroaryl" refers to a unsubstituted heteroaryl group as defined above in which one or more of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted alkyl groups and substituted aryl groups. Representative substituents include straight and branched chain alkyl groups-CH3, -C2^H5 _> -CH2OH, -OH, -OCH3, -OC2H5, - OCF3, -OC(=0)CH_3j -OC(=0)NH₂₎ -OC(=0)N(CH₃)_2; _CN, -N0₂ , -C(=0)CH₃, - C0₂H, -CO2CH3, -CONH₂, -NH₂,-N(CH₃)₂, -NHSC7CH3, -NHCOCH3, - NHC(=0)OCH₃, -NHSO2CH3, -S0₂CH₃, -S0₂NH₂ and halo.

[0087] As used herein, the term "hetero-biaryl" (when used as a group or as part of a group) refers to a biaryl group containing the specified number of atoms and which contains one or more nitrogen, sulphur, or oxygen heteroatoms. Examples of hetero-biaryl as used herein include, but are not limited to; quinoline, isoquinoline, quinoxaline, and benzotriazine groups. Said hetero-biaryl groups may be optionally substituted. In some embodiments, the substitutions may be one or more groups selected from Ci-C3alkyl, Ci-C₃alkoxy,— C(0)Me, C0₂H, C0₂Me and =0.

[0088] As used herein, the term "heterocyclyl" (Hetcy) unless otherwise specified, means mono- and bicyclic saturated rings and ring systems containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. Examples of "heterocyclyl" include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, 1 ,4-dioxanyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl and the like. Heterocyclys can also exist in tautomeric forms, e.g., 2- and 4-pyridones. Heterocyclys moreover includes such moieties in charged form, e.g., piperidinium.

[0089] As used herein, the term "hydroxy" or "hydroxyl" refers to the group -OH.

[0090] As used herein, the term "inhibition" or "inhibit" refers to a reduction of activity as compared to a control (e. g., activity in the absence of such inhibition). It is understood that inhibition can mean a slight reduction in activity to the complete ablation of all activity. An "inhibitor" can be anything that reduces activity. An "inhibitor" can act directly or indirectly. For example, inhibition of an inflammation reaction caused by an ischemic condition can be achieved by activating a GPR109 A receptor using an agonist of the GPR109A receptor. In this example, if the amount of inflammation is reduced in the presence of the GPR109A agonist as compared to the inflammation in the absence of the GPR109A agonist, the GPR109A agonist can be said to inhibit the inflammation.

[0091] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed

"stereoisomers." "Stereoisomer" and "stereoisomers" refer to compounds that exist in different stereoisomeric forms if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual

stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers.

Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture". Unless otherwise indicated, the description of a GPR109A agonist is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of MARCH'S ADVANCED ORGANIC CHEMISTRY, 5th edition M. B. Smith & J. March, John Wiley and Sons, New York, 2001 or STEREOCHEMISTRY OF ORGANIC

COMPOUNDS, E.L. Eliel & S.H. Wilen,, J. Wiley & Co, New York, 1994).

[0092] As used herein, a "label" or "radiolabel" is a composition detectable by

spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful radiolabels include, but are not limited to, ³H, ⁿC, ^{l 8}F, ^{l s}O, ^{! 3}N, ⁷⁶Br, ^99mTc, ^94mTc, ^{1 3}I, ^l24I, or ^{l 25}I, or other entities which can be made detectable, e.g., by incorporating a label into a compound, such as a GPR109A agonist, described herein.

[0093] As used herein, the term "level of GPR109A receptor mRNA" in a biological sample refers to the amount of mRNA transcribed from a GPR109A receptor gene that is present in a cell or a biological sample. The mRNA generally encodes a functional

GPR109A receptor protein, although mutations may be present that alter or eliminate the function of the encoded protein. A "level of GPR109a receptor mRNA" need not be quantified, but can simply be detected, e.g., a subjective, visual detection by a human, with or without comparison to a level from a control sample or a level expected of a control sample.

[0094] As used herein, the term "level of GPR109A receptor protein" or "level of

GPR109A receptor polypeptide" in a biological sample refers to the amount of polypeptide translated from a GPR109A receptor mRNA that is present in a cell or biological sample. The polypeptide may or may not have GPR 109A receptor protein activity. A "level of GPR109A receptor protein" need not be quantified, but can simply be detected, e.g., a subjective, visual detection by a human, with or without comparison to a level from a control sample or a level expected of a control sample.

[0095] As used herein, the term "ligand" refers generically to a molecule which binds specifically to a receptor or antigen on a cell surface.

[0096] As used herein, the term "mammalian cell" includes reference to a cell derived from a mammal, including, but not limited to, human, rat, mouse, guinea pig, chimpanzee, or macaque. The cell may be cultured in vivo or in vitro. [0097] The terms "optional" or "optionally" as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocyclo group optionally mono- or di- substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclo group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.

[0098] "Optionally substituted " means a ring which is optionally substituted independently with substituents. A site of a group that is unsubstituted may be substituted with hydrogen. [0099] The term "pharmaceutically acceptable" refers to compositions that are

physiologically tolerable and do not typically produce an allergic or similar untoward reaction when administered to a subject, preferably a human subject. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of a Federal or state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0100] As used herein, the term "physiologically functional derivative" refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example an ester or an amide thereof, and includes any pharmaceutically acceptable salt, ester, or salt of such ester of a compound of the present invention which, upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite or residue thereof. It will be appreciated by those skilled in the art that the compounds of the present invention may be modified to provide physiologically functional derivatives thereof at any of the functional groups in the compounds, and that the compounds of the present invention may be so modified at more than one position.

[0101] As used herein, the term "prodrug" refers to a compound, which is a drug precursor and which, following administration and absorption, releases the drug in vivo via some metabolic process. The term "prodrug" as used in this application also refers to a precursor or derivative form of a pharmaceutically active substance that is less cytotoxic to a cell compared to the parent drug and is capable of being enzymatically activated or converted into the more active parent form. See, e.g., Wihnan, "Prodrugs in Cancer Chemotherapy" Biochemical Society Transactions, 14, pp. 375-382, 61 5th Meeting Belfast ( 1986) and Stella et al., "Prodrugs: A Chemical Approach to Targeted Drug Delivery," Directed Drug Delivery, Borchardt et al, (ed.), pp. 247-267, Humana Press (1985).

[0102] As used herein; the terms "purified," "isolated," or "biologically pure" refer to material that is substantially or essentially free from components that normally accompany it as found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis, high performance liquid chromatography, or mass spectroscopy. A protein, a nucleic acid, a compound (such as an agonist described herein) that is the predominant species present in a preparation is substantially purified. Preferably, it means that in some embodiments of the present invention, the nucleic acid, protein, or compound is at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure; at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, more preferably at least 95% pure, more preferably at least 96% pure, more preferably at least 97% pure, more preferably at least 98% pure and most preferably at least 99% pure. "Purify" or "purification" in other embodiments means removing at least one contaminant from the composition to be purified. In this sense, purification does not require that the purified compound be homogenous, e.g., 100% pure.

[0103] As used herein, the terms "radioligand" refer to a compound, such as a GPR109A agonist described herein, into which a radionuclide suitable for PET (positron emission tomography) or SPECT (single photon emission computed tomography) scanning is incorporated. Useful radionuclides are isotopes with short half-lives, such as "C, ^{l 3}N, ^{l 5}0, ^{l 8}F, ⁷⁶Br, ^{, 23}1, ¹²⁴I, and ^{l 25}I, and. The terms also refer to a compound in which a radionuclide suitable for detection by other means has been incorporated (e.g., ³H or ^{l 23}I for detection by scintigraphy or autoradiography).

[0104] As used herein, the term "salt" refers to a salt of a compound, such as a GPR109A agonist described herein, which is prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobrpmic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., 1977, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 66: 1 -19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0105] The neutral forms of a compound, such as a GPR109A agonist described herein, may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

[0106] As used herein, the term "solvate" refers to a compound of the present invention that is complexed to a solvent. Solvents that can form solvates with compounds of the present invention include common organic solvents such as alcohols (methanol, ethanol, etc.), ethers, acetone, ethyl acetate, halogenated solvents (methylene chloride, chloroform, etc.), hexane and pentane. Additional solvents include water. When water is the complexing solvent, the complex is termed a "hydrate."

[0107] As used herein, the term "subject" refers to an individual. Preferably, the subject is a mammal such as a primate, and, more preferably, a human. The term "subject" can include domesticated animals, such as cats, dogs, etc., livestock (e. g. , cattle, horses, pigs, sheep, goats, etc. ), and laboratory animals (e. g. , mouse, rabbit, rat, guinea pig, etc.). In some embodiments, the term subject refers to a patient. In other embodiments the term "subject" refers to a patient having an ischemic condition.

[0108] As used herein, the term "substantially free" or similar grammatical equivalents refers to a preparation of a compound of interest, such as a GPR109A agonist described herein, which does not include detectable amounts of impurities which would inhibit, block or interfere with a function or activity of the compound of interest. [0109] Each of the terms herein (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") is meant to include both "unsubstituted" and optionally "substituted" forms of the indicated radical, unless otherwise indicated. Typically each radical is substituted with 0, 1 , 2, 3, 4, or 5 substituents, unless otherwise indicated. Examples of substituents for each type of radical are provided below.

[0110] As used herein, the term "substituted" refers to a group as defined herein in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atom "substituents" such as, but not limited to, a halogen atom such as F, CI, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy, and acyloxy groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amino, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, alkoxyamino, hydroxyamino, acylamino, sulfonylamino, N-oxides, imides, and enamines; and other heteroatoms in various other groups. "Substituents" also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, acyl, amido, alkoxycarbonyl, aminocarbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. "Substituents" further include groups in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to a cycloalkyl, heterocyclyl, aryl, and heteroaryl groups. Representative "substituents" include, among others, groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluoro, chloro, or bromo group. Another representative "substituent" is the trifiuoromethyl group and other groups that contain the trifiuoromethyl group. Other representative "substituents" include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy group. Other representative "substituents" include alkyl groups that have an amine, or a substituted or unsubstituted alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, diheterocyclylamine, (alkyl)(heterocyclyl)amine, or (aryl)(heterocyclyl)amine group. Still other representative "substituents" include those in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to an alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group.

[0111) The herein-defined groups may include prefixes and/or suffixes that are commonly used in the art to create additional well-recognized substituent groups. As examples,

"alkylamino" refers to a group of the formula -NR^aRb. Unless stated otherwise, for the following groups containing R^a, R , RC, Rd _ancj Re_: Ra, _ancj j^b _eacn independently selected from H, alkyl, alkoxy, thioalkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl or are optionally joined together with the atom(s) to which they are attached to form a cyclic group. When R^a and R are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NR^aR^b is meant to include 1 -pyrrolidinyl and 4-morpholinyl.

[0112] R^C, Rd, Re _and Rf are each independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or alkylenearyl as defined herein.

[0113] Typically, a particular radical will have 0, 1 , 2, or 3 substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, a radical will be unsubstituted or monosubstituted. Most preferably, a radical will be unsubstituted.

[0114] "Substituents" for the alkyl and heteroalkyl radicals (as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocyclyl) can be a variety of groups selected from: -OR^a, =0, =NR^a, =N-OR^a, -NR^aR^b, -SR^a, halogen,

-SiR^aR^bR^c, -OC(0)R^a, -C(0)R^a, -C0₂R^a, -CONR^aR^b, -OC(0)NR^a R^b, -NR^bC(0)R^a,

-NR^a-C(0)NR^bR^c, -NR^a"S0₂NR^bR^c, -NR^bC0₂R^a, -NH-C(NH₂)=NH, -NR^aC(NH₂)=NH,

-NH-C(NH₂)=NR^a, -S(0)R^a, -S0₂R^a, -S0₂NR^aR^b, -NR^bS0₂R, -CN and -N0₂, in a number ranging from zero to three, with those groups having zero, one or two substituents being particularly preferred.

[0115] In some embodiments, "substituents" for the alkyl and heteroalkyl radicals are selected from: -OR^a, =0, - NR^aR^b, -SR^a halogen, -SiR^aR^bR^c, -OC(0)R^a, -C(0)R^a, -CO 2R^a, -CONR^aR^b, -OC(0)NR^aR^b, -NR^bC(0)R^a, -NR^bC0₂R^a, -NR^aS0₂NR R^c, -S(0)R^a, -S0₂R^a, -S0₂NR^aR^b, -NR^cS0₂R, -CN and -N0₂, where R^a and R^b are as defined above. In some embodiments, substituents are selected from: -OR^a, =0, - NR^aR , halogen, -OC(0)R^a, -C0₂R^a, -CONR^aR , -OC(0)NR^aR^b -NR^bC(0)R^a, -NR^bC0₂R^a, -NR^a-S0₂NR^bR^c, -S0₂R^a, -S0₂NR^aR^b, -NR"S0₂R, -CN and -N0₂.

[0116] Examples of substituted alkyl are: -<CH₂)3NH₂, -(CH₂)3NH(CH₃),

-(CH₂)3NH(CH₃)₂, -CH₂C(=CH₂)CH₂NH_2; -CH₂C(=0)CH₂NH_2> -CH₂S(=0)₂CH₃₅ - CH₂ OCH₂NH ₎ -C0₂H Examples of substituents of substituted alkyl are: CH₂OH, -OH, -OCH₃, -OC₂H₅, -OCF3, -OC(=0)CH₃₎ -OC(=0)NH_2j -OC(=0)N(CH₃)₂₎ -CN, -N0₂, - C(=0)CH₃, -C0₂H, -C0₂CH₃, -CONH₂, -NH₂ ,-N(CH₃)₂, -NHS0₂CH₃, -NHCOCH₃, -NHC(=0)OCH₃, -NHS0₂CH₃, -S0₂CH₃, -S0₂NH₂, and halo.

[0117] Similarly, "substituents" for the aryl and heteroaryl groups are varied and are selected from: -halogen, -OR^a, -OC(0)R^a, -NR^aR^b, -SR^a, -R^a, -CN, -N0₂, -C0₂R^a,

-CONR^aR^b, -C(0)R^a, -OC(0)NR^aR^b, -NR^bC(0)R^a, -NR^bC(0)₂R^a, -NR^aC(0)NR^bR^c,

-NH-C(NH₂)=NH, -NR^aC(NH₂)=NH, -NH-C(NH )=NR^a , -S(0)R^a, -S(0)₂R^a,

-S(0)₂NR^aR^b -N₃, -CH(Ph)₂, perfluoroCi.galkoxy, and perfluoroC|.₈alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R^a, R^b and R^c are independently selected from hydrogen, C|_6alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-Ci.₈alkyl, and (unsubstituted aryl)oxy-Ci_₈alkyl.

[0118] Two or three of the "substituents" on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(0)-(CH₂)q-U-, wherein T and U are independently -NH-, -0-, -CH₂- or a single bond, and q is 0, 1 or 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH₂)_r-B-, wherein A and B are independently

-CH₂-, -0-, -NH-, -S-, -S(O)-, -S(0)₂-, -S(0)₂NR^a" or a single bond, and r is 1 , 2 or 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH₂)_s-X-(CH₂)_r -, where s and t are independently integers of from 0 to 3, and X is -0-, -NR^a", -S- , -S(O)-, -S(0)₂-, or

-S(0)₂NR^a". The substituent R^a in -NR^a" and -S(0)₂NR^a- is selected from hydrogen or , unsubstituted C|.₆alkyl. Otherwise, R' is as defined above.

[0119] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-0-C(0)-

[0120] As used herein, the terms "treat," "treating," and "treatment" refer to administering a composition to a subject having an undesired disease, disorder, or condition or is at risk for developing such undesired disease, disorder, or condition. The condition can be any pathogenic disease, autoimmune disease, cancer or an inflammatory condition. The effect of the administration of the composition to the subject can have the effect of, but is not limited to, (i) reducing a symptom(s) of the condition, (ii) a reduction in the severity of the condition, or (iii) the complete ablation of the condition. The terms include: (i) preventing a disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be predisposed to the disease but does not yet experience any symptoms of the disease; (ii) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; or (iii) relieving the disease, i.e. causing regression of the disease or its clinical symptoms. The terms refer to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disease or undesired condition as well as those in which the disease or undesired condition is to be prevented.

Hence, a mammal may have been diagnosed as having the disease or undesired condition or may be predisposed or susceptible to the disease.

II. COMPOSITIONS

A. GPR109A Agonists

1. GPR109A

[0121] A G-protein coupled receptor that binds nicotinic acid has been identified (Soga et al., 2003, Biochem Biophys Res Comm n 303 :364-369; Tunaru et al. , 2003, Nat Med 9:352- 325; Wise et al., 2003, J Biol Chem 278:9869-74). The receptor termed GPR109A (HM74A in human and PUMA-G in mice) is expressed in adipocytes and immune cells and couples to G-proteins of the Gj family (Fig. 1 A). Activation of the receptor by nicotinic acid decreases the activity of hormone-sensitive lipase via lowering of c AMP levels which results in a reduced hydrolysis of triglycerides to free fatty acids (Fig. IB). GPR109A has been described as the receptor mediating the antilipo lytic effects of nicotinic acid (Tunaru et al., 2005, Mol Pharmacol 68(5): 1271-80).

[0122] Multiple functions with respect to its involvement in regulating lipid metabolism have been attributed to GPR109A, however, hitherto, as much as Applicants are aware, nothing suggested that GPR109A is involved in the treatment, prevention, or alleviation of an ischemic condition. Applicants herewith describe for the first time that GPR109 A agonists can be used in methods for the treatment, prevention, and alleviation of an ischemic condition. The following describes GPR 109A agonists useful in practicing methods of the present invention. According to Applicants' believe, GPR109A agonists have not been used as such to treat, prevent, or alleviate an ischemic condition prior to Applicants' invention. [0123] Some of the GPR109A agonists are currently used in clinical applications and thus, are well tolerable by a subject. For example, nicotinic acid is in clinical use to treat hyperlipidemia which in some cases may lead to stroke. Here, Applicants surprisingly and unexpectedly have found that GPR109A agonists protect against acute stroke independent from the lipid lowering effect some of these agonists may have.

[0124] Each of the GPR109A agonists described herein may be provided as a compound as · represented by a formula shown or as a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

2. Nicotinic Acid

[0125] In some embodiments of the present invention, a GPR109A agonist is nicotinic acid (pyridine-3-carboxylic acid; CAS number 59-67-6) a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. Nicotinic acid is an agonist for the high-affinity nicotinic receptor, G-coupled receptor 109A (GPR109A; Tunaru et al, 2003, Nat Med 9:352-325). It occurs naturally in plants and animals, and is also added to many foods as a vitamin supplement. Niacin is also present in many multiple vitamins and nutritional supplements. Nicotinic acid can be obtained, e.g., from Sigma (St. Louis, MO).

[0126] Nicotinic acid, also called niacin, is a B vitamin (vitamin B3) and is widely used as a drug for decades in the treatment of hyperlipidemia. Currently, niacin is used to treat and prevent a lack of natural niacin in the body, and to lower cholesterol and triglycerides (types of fat) in the blood.

[0127] In some embodiments, a GPR109A agonist is nicotinic acid, a compound

represented by Formula (I):

[0128] GPR109 A is coupled to the inhibitory G protein Gj. Activation of the receptor with its ligands or GPR109A agonists described herein, results in a pertussis toxin-sensitive decrease in cAMP levels. One of the actions of cAMP in adipocytes is to stimulate the hormone-sensitive lipase by protein phosphorylation, which leads to triglyceride hydrolysis and release of free fatty acids into the circulation. Niacin, by its ability to reduce cAMP levels, decreases the activity of lipases and prevents the release of free fatty acids from fat stores (Gille et al, 2008, Annu Rev Pharmacol Toxicol 48:79-106).

[0129] The therapeutic value of nicotinic acid is limited by its major side effect, cutaneous flushing, a burning sensation felt on the face and upper body. However, due to the severity of an ischemic condition described herein and the relatively short time window during which a GPR109A agonist should be applied to a subject afflicted with such ischemic condition, such as cerebral ischemia, side effects of nicotinic acid may well be acceptable.

3. Nicotinic Acid Derivatives

a) Complamin^®

[0130] In some embodiments of the present invention, a GPR109A agonist is Complamin^® (Xanthinol-nicotinate; Hotz, 1983, Nicotinic Acid and its Derivatives: a Short Survey. In Advances of Lipid Research (Paoletti R., Kritchevsky D., eds), Vol 20, New York: Academic Press, pp 195-217; Cultrera et al., \97 \ , Arzneim. Forsch. 21 :954) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

(0131] In some embodiments, a GPR109A agonist is Complamin^®, a compound represented by Formula (II):

[0132] Formulations of Complamin^® are also known as Angioamin^®, Complamex^®, Stenalgil^®, Contamex^®, Landrina^®, Sadamine^®, Teoicol^®, Xanidil^®, and Vedrin^® The IUPAC name is 7-[2-hydroxy-3-[2-hydroxyethyl(methyl)amino]propyl]-l ,3-dimethylpurine 2,6-dione; pyridine-3-carboxylic acid. Administration and dosing of Complamin in subjects, including humans, is known in the art (Hotz, 1983, Nicotinic Acid and its

Derivatives: a Short Survey. In Advances of Lipid Research (Paoletti R., Kritchevsky D., eds), Vol 20, New York: Academic Press, pp 195-21 7; Cultrera et ai , 1971 , Arzneim. Forsch. 21 :954).

b) Pericit^®

[0133] In some embodiments of the present invention, a GPR109A agonist is Pericit^® (Niceritrol (pentaerythritol tetranicotinate, PETN); Hotz, 1983, Nicotinic Acid and its Derivatives: a Short Survey. In Advances of Lipid Research (Paoletti R., Kritchevsky D., eds), Vol 20, New York: Academic Press, pp 195-217; Olson et al, 1974, Artherosclerosis 19:61 ; Brattsand and Harthon, 1971, Arzneim Forsch 21 : 1335; Harthon and Sigroth, 1974, Arzneim Forsch 24: 1688) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0134] In some embodiments, a GPR109A agonist is Pericit^®, a compound represented by Formula (III):

[0135] Pericit^® is an approved drug, however, hitherto to Applicants' knowledge has not been used for the treatment of an ischemic condition as described herein. Administration and dosing of Pericit^® in subjects, including humans, is known in the art.

c) Hexanicit^®

[0136) In some embodiments of the present invention, a GPR109 A agonist is Hexanicit^® (Mesoinositol-tetranicotinate (MIHN); Hotz, 1983, Nicotinic Acid and its Derivatives: a Short Survey. In Advances of Lipid Research (Paoletti R., Kritchevsky D., eds), Vol 20, New York: Academic Press, pp 195-217; Harthorn and Brattsand, 1979, Arzneim. Forsch 29: 1859) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0137] In some embodiments, a GPR109A agonist is Hexanicit^®, a compound represented by Formula (IV):

wherein R is

[0138] Hexanicit^® is an approved drug, however, hitherto to Applicants' knowledge has not been used for the treatment of an ischemic condition as described herein. Administration and · dosing of Hexanicit^® in subjects, including humans, is known in the art.

d) Bradilin"

[0139] In some embodiments of the present invention, a GPR1 09 A agonist is Bradilin^® (Tetranicotinoylfructose; Hotz, 1983, Nicotinic Acid and its Derivatives: a Short Survey. In Advances of Lipid Research (Paoletti R., Kritchevsky D., eds), Vol 20, New York: Academic Press, pp 195-21 7; Benaim and Dewar, 1975, J Int Med Res 3 :423; Salmi and Frey, 1974, Curr Ther Res 16:669) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0140] In some embodiments, a GPR109A agonist is Bradilin^®, a compound represented by Formula (V):

wherein R is

[0141] Bradilin^® is an approved drug, however, hitherto to Applicants' knowledge has not been used for the treatment of an ischemic condition as described herein. Administration and dosing of Bradilin^® in subjects, including humans, is known in the art. e) Sorbinicate

[0142] In some embodiments of the present invention, a GPR 109A agonist is Sorbinicate (nicotinic acid hexaester of sorbitol; glucitol hexanicotinate; D-Glucitol hexa; CAS No. 61 84- 06- 1 ; Hotz, 1983, Nicotinic Acid and its Derivatives: a Short Survey. In Advances of Lipid Research (Paoletti R., Kritchevsky D., eds), Vol 20, New York: Academic Press, pp 195-217; Avogaro et ai , 1977, Pharmacol Res Commun 9:599; Avogaro et al, 1978, Pharmacol Res Commun 10: 127; Subissi et ai, 1980, Arzneim Forsch 30: 1278) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0143] In some embodiments, a GPR109A agonist is Sorbinicate, a compound represented by Formula (VI):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. [0144] Sorbinicate is an approved drug, however, hitherto to Applicants' knowledge has not been used for the treatment of an ischemic condition as described herein. Administration and dosing of Sorbinicate in subjects, including humans, is known in the art.

f) Lipo-Merz^®

[0145] In some embodiments of the present invention, a GPR109A agonist is Lipo-Merz^® (Etofibrate; Hotz, 1983, Nicotinic Acid and its Derivatives: a Short Survey. In Advances of Lipid Research (Paoletti R., Kritchevsky D., eds), Vol 20, New York: Academic Press, pp 195-217; Mertz et ai, 1982, Med Welt 33:405; Spottl and Froschauer, 1976, Artherosclerosis 25:293) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. IUPAC name of Lipo-Merz® is 2-[2-(4-chlorophenoxy)-2- methylpropanoyl]oxyethyl pyridine-3-carboxylate.

[0146] In some embodiments, a GPR109A agonist is Lipo-Merz^®, a compound represented by Formula (VII):

[0147] Formulations of Lipo-Merz^® are known in the art as Etofibrate^®, Etofibrato^®, and Etofibratum^®. Lipo-Merz^® is an approved drug, however, hitherto to Applicants' knowledge has not been used for the treatment of an ischemic condition as described herein.

Administration and dosing of Lipo-Merz^® in subjects, including humans, is known in the art.

g) Arterium^®

[0148] In some embodiments of the present invention, a GPR109A agonist is Arterium^® (nicofibrate; 2-(p-Chlorophenoxy)-2-methylpropionic acid (pyridin-3-yl)methyl ester; CAS No. 31980-29-7; Hotz, 1983, Nicotinic Acid and its Derivatives: a Short Survey. In Advances of Lipid Research (Paoletti R., Kritchevsky D., eds), Vol 20, New York: Academic Press, pp 195-217; Marmo et ai, 1971 , Farmaco Prat 26:557) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0149] In some embodiments, a GPR 109A agonist is Arterium^®, a compound represented by Formula (VIII):

[0150] Arterium^® is an approved drug, however, hitherto to Applicants' knowledge has not been used for the treatment of an ischemic condition as described herein. Administration and dosing of Arterium^® in subjects, including humans, is known in the art.

h) Cortofludan^®

[0151] In some embodiments of the present invention, a GPR109A agonist is Cortofludan^® (ciclonicate; Hotz, 1983, Nicotinic Acid and its Derivatives: a Short Survey. In Advances of Lipid Research (Paoletti R., Kritchevsky D., eds), Vol 20, New York: Academic Press, pp 195-217; Rimondi et al. , 1980, Int Symp Drugs Affect Lipid Metab 7^th Milan, May 28 Abstr. p. 180) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0152] In some embodiments, a GPR109A agonist is Cortofludan^®, a compound represented by Formula (IX):

[0153] Cortofludan^® is an approved drug, however, hitherto to Applicants' knowledge has not been used for the treatment of an ischemic condition as described herein. Administration and dosing of Cortofludan^® in subjects, including humans, is known in the art.

i) Ronicol^®

[0154] In some embodiments of the present invention, a GPR109 A agonist is Ronicol^® (β- Pyridylcarbinol, Hotz, 1983, Nicotinic Acid and its Derivatives: a Short Survey. In Advances of Lipid Research (Paoletti R., Kritchevsky D., eds), Vol 20, New York: Academic Press, pp 195-217; Zollner and Gudenzi, 1966, Med Klin 61 , 2036; Zollner and Wolfram, 1970,

Hautarzt 21 :443) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0155] In some embodiments, a GPR109A agonist is Ronicol^® a compound represented by Formula (X):

[0156] Ronicol^® is an approved drug, however, hitherto to Applicants' knowledge has not been used for the treatment of an ischemic condition as described herein. Administration and dosing of Ronicol^® in subjects, including humans, is known in the art.

4. Acipimox

[0157] In some embodiments of the present invention, a GPR109A agonist is acipimox (5- methylpyrazine carboxylic acid 4-oxide or 5-carboxy-2-methyl-l-oxidopyrazin-l-ium, a niacin derivative (CAS number 51037-30-0); Soga et al, 2003, Biochem Biophys Res Commun 303:364-369; Wise et al, 2Wi, JBiol Chem 278:9869-74) a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0158] In some embodiments, a GPR109A agonist is acipimox, a compound represented by Formula (XI): '

[0159] Acipimox in high doses up to 2,250 mg/d was well tolerated except for initial gastric complaints and of flushing (Stuyt et al, 1998, Neth JMed 53(5):228-33). Acipimox is available in capsules form as OLBETAM^®, each capsule containing 250 mg acipimox. Acipimox is known to inhibit the release of fatty acids from adipose tissue and to reduce the blood concentration of very low density lipoproteins (VLDL or pre-beta) and low density lipoproteins (LDL or beta) with a subsequent overall reduction in triglyceride and cholesterol levels. Acipimox is rapidly and completely absorbed orally, reaching peak plasma levels within two hours. The half-life is about two hours. It is not significantly metabolized except in the elderly and is eliminated almost completely intact by the urinary route. Until hitherto, the use of apicimox in a method of the present invention has not been known.

5. Acifran

[0160] In some embodiments of the present invention, a GPR109A agonist is acifran (4,5- dihydro-5-methyl-4-oxo-5-phenyl-2-furancarboxylic acid; CAS number 72420-38-3 Cayen et al., 1982, Atherosclerosis 45:281-290; LaRosa et al, 1987, Artery 14:338-350) or a pharmaceutically acceptable salt or solvate thereof. Acifran can be obtained, e.g., from Tocris Cookson, Inc. (Cat No. 1762; Bristol, UK).

[0161] Acifran is a GPR109A and GPR109B agonist. In some embodiments, a GPR109A agonist is acifran as represented by Formula (XII):

[0162] Acifran. is known as a hypolipidaemic agent; more potent than nicotinic acid and clofibrate. Full and potent agonist at the human GPCR HM74A/GPR109A and GPR109B (EC50 values are 1.3 and 4.2 μΜ respectively). In vivo, it reduces serum triglycerides and circulating LDL-cholesterol without affecting liver weight or liver enzymes. Until hitherto, the use of acifran in a method of the present invention has not been known.

6. Acifran Analogs

[0163] In some embodiments of the present invention, a GPR 109A agonist is an acifran analog as described by Jung et al., 2007, J Med Chem 50(7): 1445-8; incorporated herewith by reference in its entirety). Is some embodiments, an acifran analog is an acifran phenyl analog represented by Formula (XIII):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, wherein:

Ri is Ph, vinyl, Ethyl, 1 -spiro, spirocyc, 1 -cyclopentenyl, 1 -cyclohexenyl, 3- pyrimidine. 4-pyrimidine, 2-furan, 2,5-diCl-Ph, 2,4-diF-Ph, 3,4-diF-Ph, 2,6-diF-Ph, 3,5-diF- Ph, 2-F-Ph, 4-F-Ph. 3-F-Ph, 3-Cl-Ph, 3-Br-Ph, 3-I-Ph, 3-Me-Ph, 3-Et-Ph, 3-CF₃-Ph, or 3- OMe-Ph; and

R2 is Me, Et, indane, or lopetane.

[0164] Is some embodiments of the present invention, an acifran analog is an acifran thiophene analog represented by Formula (XIV):

Ri is 2-thienyl, 5-Cl-2-thienyl, 5-Me-2-thienyl, 4-Br-2thienyl, 4-Me-2-thienyl, 4-Br- 5-Me-2-thienyl, 3-thienyl, 5-Cl-3-thienyl, 5-Br-3-thienyl, or 5-Me-3-thienyl.

[0165] Jung et al. describe synthetic pathways for preparing phenyl and thiophene analogs of acifran and the respective EC50 for binding to GPR109A and the related receptor, GPR109B. Jung et al., however, did not suggest to use an acifran analog GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0166] In some embodiments of the present invention, a GPR109 A agonist is an acifran analog as described by Boatman et al. (2008, J Med Chem 51(24):7653-62; incorporated herewith by reference in its entirety). [0167] In some embodiments of the present invention, a GPR109A agonist is an acifran derivative GPR109A agonist (compound 17 of Boatman et al.) represented by Formula (XV):

[0168] In some embodiments of the present invention, a GPRl 09 A agonist is an acifran derivative GPRl 09 A agonist (compound 1 8 of Boatman et al.) represented by Formula (XVI):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, wherein R is methyl or i-propyl.

[0169] In some embodiments of the present invention, a GPR109A agonist is an acifran derivative GPR109A agonist (compound 19 of Boatman et al.) represented by Formula (XVII):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, wherein R is Mt-butyl or 4-FPh. [0170| In some embodiments of the present invention, a GPR109A agonist is an acifran derivative GPR109A agonist (compound 20 of Boatman et al.) represented by Formula (XV111):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, wherein X is H, or halogen, preferably, CI or Br.

[0171] In some embodiments of the present invention, a GPR109A agonist is an acifran derivative GPR109A agonist (compound 21 of Boatman et al.) represented by Formula (XIX):

[0172] In other embodiments of the present invention, a GPR109A agonist is an acifran analog as described by Mahboubi et ai, 2006, Biochem Biophys Res Commun 340(2):482-90; incorporated herewith by reference in its entirety). Mahboubi et α/.did not suggest to use an acifran analog GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

7. Monomethylfumarate

[0173] In some embodiments of the present invention, a GPR109 A agonist is

monomethylfumarate (CAS number 2756-87-8; Tang et ai, 2008, Biochem Biophys res Comm 375(4): 562-5; incorporated herewith by reference in its entirety) as represented by Formula (XX):

|0174] Monomethylfumarate is the active metabolite of the psoriasis drug Fumaderm. Tang et al. showed that monomethylfumarate activates GPR109A in a calcium based aequorin assay, cAMP assay and demonstrated competitive binding with nicotinic acid (2008, Biochem Biophys Res Comm 375(4):562-5). Tang et al. suggested that niacin should be investigated to treat psoriasis in addition to its role in treating lipid disorders (2008, Biochem Biophys Res Comm 375(4):562-5). Tang et al., however, did not suggest to use

monomethylfumarate in a method to treat, prevent, or alleviate an ischemic condition.

8. Pyrazole GPR109A Agonists

[0175] In some embodiments of the present invention, a GPR109 A agonist is a pyrazole GPR109A agonist as set forth herein.

[0176] In some embodiments of the present invention, a GPR109A agonist is a GPR109A acyl hydroxypyrazole agonist. GPR109A acyl hydroxypyrazole agonists useful for practicing methods of the present invention are described , e.g., in WO2008/051403; incorporated herewith by reference in its entirety). In this publication, the acyl hydroxypyrazole were described as being useful in potential therapy to reduce free fatty acids, low-density lipoprotein cholesterol, total cholesterol, and serum triglycerides, and to raise high-density lipoprotein cholesterol. Diseases that potentially could be treated using these GPR109A agonists included dyslipidemia, atherosclerosis, and metabolic syndromes such as diabetes {see also, Shen, 2009, Expert Opin Ther Pat 19(8): 1 149-55; Shen and Colletti, 2009, Expert Opin Ther Pat 19(7):957-67).

[0177] In some embodiments of the present invention, a GPR109A agonist is a compound represented by Formula (XXI): ₂

X represents a nitrogen or carbon atom;

R⁶ represents Ci alkyl optionally substituted with 1 -3 halo groups;

the dashed lines represent optional bonds;

when the dashed line to Z represents a bond that is absent, the dashed line to (Y)_p represents a bond that is present and Z represents a group selected from OH, SH, NH₂. C0₂H and S0₃H;

each R⁴ is H or halo, or is selected from the group consisting of: a) a phenyl or a 5-6 membered heteroaryl group containing 1 heteroatom selected from O, S and N, and optionally containing 1 -3 additional N atoms, said phenyl and heteroaryl groups being optionally substituted with 1 -3 substituents, 1 -3 of which are halo, and 0- 1 of which are selected from: OH, NH₂, Ci.₃alkyl, C|.₃alkoxy, haloCi_-3alkyl and haloC].3alkoxy; and

(b) Ci.3alkyl optionally substituted with 1 -3 substituent groups, 1 -3 of which are halo atoms, and 0- 1 of which are selected from the group consisting of: OH, OCi_-3alkyl, NH_2, NHCi_-3alkyl, N(Ci.₃alkyl)₂, CN, N0₂, Hetcy, phenyl and a 5-6 membered heteroaryl group containing 1 heteroatom selected from O, S and N, and optionally containing 1 -3 additional N atoms, said phenyl and heteroaryl groups being optionally substituted with 1 -3 substituents, 1 -3 of which are halo, and 0-1 of which are selected from: OH, NH₂, C|.₃alkyl, C|.₃alkoxy, haloCi_-3alkyl and haloCi_-3alkoxy; ring A represents a 6- 1 0 membered aryl, a 5- 13 membered heteroaryl or a partially aromatic heterocyclic group, said heteroaryl and partially aromatic heterocyclic group containing at least one heteroatom selected from O, S and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1 -3 additional N atoms, with up to 5 heteroatoms being present;

R² and R³ are independently H, Ci_₃alkyl, haloCi_-3alkyl, OC].₃alkyl, haloCi_-3alkoxy, OH, NH₂ or F; n represents an integer of from 1 to 5; each R¹ is H or is selected from the group consisting of: a) halo, OH, C0₂H, CN, NH_2, S(O)₀.₂R^e wherein R^e represents C_)-4alkyl or phenyl, said Ci_-4alkyl or phenyl being optionally substituted with 1 -3 substituent groups, 1 -3 of which are selected from halo and Ci_-3alkyl, and 1 -2 of which are selected from the group consisting of: OCi-₃alkyl, haloC|.₃alkyl, haloC]-₃alkoxy, OH, NH₂ and NHC |.₃alkyl; b) C|.6 alkyl and OCi^alkyl, said group being optionally substituted with 1 -3 groups, 1 -3 of which are halo and 1 -2 of which are selected from: OH, C0₂H, C0₂Ci_-4alkyl,

C0₂C|.₄haloalkyl, OC0₂C|.₄alkyl, NH₂, NHC,-₄alkyl, N(Ci- alkyl)₂, Hetcy and CN;

■*

c) Hetcy, NHCi.₄alkyl and N(Ci.4alkyl)₂, the alkyl portions of which are optionally substituted as set forth in (b) above; d) C(0)NH₂, C(0)NHC alkyl, C(0)N(Ci_-4alkyl)₂, C(0)Hetcy, C(0)NHOC,. ₄alkyl and C(0)N(C|-₄alkyl)(OCi.₄alkyl), the alkyl portions of which are optionally substituted as set forth in (b) above; e) NR C(0)R", N R S0₂R", NR C0₂R" and NR C(0)N R wherein:

R represents H, Ci^alkyl or haloC].₃alkyl,

R" represents (a) Ci.galkyl optionally substituted with 1 -4 groups, 0-4 of which are halo, and 0-1 of which are selected from the group consisting of: OCi.6alkyl, OH, C0₂H, C0₂Ci.₄alkyl, C0₂C,.₄haloalkyl, OC0₂Ci_-4alkyl, NH₂, NHC alkyl, N(C|.

alkyl)₂, CN, Hetcy, Aryl and HAR, said Hetcy, Aryl and HAR being further optionally substituted with 1-3 halo, Ci_₄alkyl,

and haloC alko y groups;

(b) Hetcy, Aryl or HAR, said Aryl and HAR being further optionally substituted with 1-3 halo, Ci.₄alkyl, Ci_-4alkoxy, haloCi_-4alkyl and haloCi. ₄alkoxy groups; and R'" representing H or R"; and f) phenyl or a 5-6 membered heteroaryl or heterocyclic group attached at any available point and being optionally substituted with 1 -3 halo, Ci^alkyl or haloCi alkyl groups, or 1 -2 OCi^alkyl or haloOCi alkyl groups, or 1 moiety selected from the group consisting of:

i) OH; C0₂H; CN; NH₂ ; S(O)₀.₂R^e wherein R^e is as described above; ii) NHCi_-4alkyl and N(C|.₄alkyl)₂, the alkyl portions of which are optionally substituted with 1-3 groups, 1 -3 of which are halo and 1 -2 of which are selected from: OH, C0₂H, C0₂C alkyl, C0₂C_Mhaloalkyl, OCO^_Malkyl, NH₂, NHC,.₄alkyl, N(C,. ₄alkyl)₂, CN; iii) C(0)NH₂, C(0)NHCi- alkyl, C(0)N(Ci.₄alkyl)₂, C(0)NHOCi. ₄alkyl and C(0)N(C|.₄alkyl)(OCi.₄alkyl), the alkyl portions of which are optionally substituted as set forth in (b) above; and iv) NR C(0)R", NR S0₂R", NR C0₂R" and NR^"C(0)NR^"R'" wherein R , R" and R are as described above. [0178] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein Y represents a nitrogen atom unsubstituted or substituted with R⁶. Within these embodiments, all other variables are as set forth with respect to Formula (XI).

[0179] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein Y represents a carbon atom. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0180] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein p represents 1. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0181] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein p represents 2. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0182] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein the dashed line to Z represents a bond that is present and Z represents O or the dashed line to Z represents a bond that is absent and Z represents OH. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0183] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein ring B represents a phenyl ring or a 5-7 membered carbocycle.

Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0184] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein ring B represents a phenyl ring. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0185] In some embodiments of the present invention, a GPR109 A agonist of Formula

(XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein ring B represents a 5-7 membered carbocycle. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0186] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein ring A represents a 5-13 membered heteroaryl or a partially aromatic heterocyclic group, said heteroaryl and partially aromatic heterocyclic group containing at least one heteroatom selected from O, S and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1-3 additional N atoms, with up to 5 heteroatoms being present. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0187] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein ring A represents a 5- 13 membered heteroaryl group, containing at least one heteroatom selected from O, S and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1 -3 additional N atoms, with up to 5 heteroatoms being present. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0188] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein ring A represents a 5 membered heteroaryl group, containing at least one heteroatom selected from O, S and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1-3 additional N atoms, with up to 4 heteroatoms being present. Within these embodiments all other variables are as set forth with respect to Formula (XXI).

]0189] In some embodiments of the present invention, a GPR109A agonist of Formula

(XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein ring A represents a 5 membered heteroaryl group selected from the group consisting of: oxadiazole, thiazole, pyrazole, triazole and oxazole. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0190] In some embodiments of the present invention, a GPR109A agonist of Formula

(XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein ring A represents a 5 membered heteroaryl group selected from the group consisting of: oxadiazole and pyrazole. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0191] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein n represents 2, 3 or 4. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0192] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein n represents 2. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0193] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R² and R³ are selected from the group consisting of: H, Cualkyl, OH and NH₂, with no more than one being OH or NH₂. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0194] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R² and R³ are selected from the group consisting of: H,

and NH₂, with no more than one being NH₂. Within these embodiments all other variables are as set forth with respect to Formula (XXI).

[0195] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R² and R³ are selected from the group consisting of: H, CH3 and NH₂, with no more than one being NH₂. Within these embodiments, all other variables are as set forth with respect to Formula (XXI).

[0196] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein each R¹ is H or is selected from the group consisting of:

a) halo, OH and NH₂;

b) NR'S0₂R" wherein R' represents H, C_]-3alkyl or haloCi_-3alkyl, and R" represents

Hetcy, Aryl or HAR, said Aryl and HAR being further optionally substituted with 1 -3 halo, Ci^alkyl, Ci_-4alkoxy, haloC|_-4alkyl and haloCi.₄alkoxy groups; and c) phenyl or a 5-6 membered heteroaryl or heterocyclic group attached at any available point and being optionally substituted with 1-3 halo, C_halky 1 or haloCualkyl groups, or 1 -2 OCi.₃alkyl or haloOCi.3alkyl groups, or 1 moiety selected from the group consisting of OH and N¾.

[0197] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein each R¹ is H or is selected from the group consisting of:

a) halo or OH;

b) NR'S0₂R" wherein R' represents H, C|.₃alkyl or haloC|.₃alkyl, and R" represents

Hetcy, Aryl or HAR, said Aryl and HAR being further optionally substituted with 1 -3 halo, C|_₄alkyl, Ci_₄alkoxy, haloC|.₄alkyl and haloC|.₄alkoxy groups; and

c) phenyl or a 5-6 membered heteroaryl group attached at any available point and being optionally substituted with 1 -3 halo, methyl or halomethyl groups, or 1 moiety selected from the group consisting of OH and NH₂.

Within these embodiments all other variables are as set forth with respect to Formula (XXI).

[0198] In some embodiments of the present invention, a GPR109A agonist of Formula (XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein each R¹ is H or is selected from the group consisting of:

a) halo or OH and

b) phenyl or a 5-6 membered heteroaryl group attached at any available point and being optionally substituted with 1 -3 halo, methyl or halomethyl groups, or 1 moiety selected from the group consisting of OH and NH₂.

[0199] In some embodiments of the present invention, a GPR109A agonist of Formula

(XXI) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein:

Y represents a carbon or nitrogen atom;

p represents 1 or 2, such that when p represents 2, no more than one Y represents nitrogen; the dashed lines represent optional bonds; when the dashed line to Z represents a bond that is present, Z represents O; and the dashed line to (Y)p represents a bond that is absent, and when the dashed line to Z represents a bond that is absent, the dashed line to (Y)p represents a bond that is present and Z represents OH;

ring B represents a phenyl ring or a 5-7 membered carbocycle;

ring A represents a 5-13 membered heteroaryl or a partially aromatic heterocyclic group, said heteroaryl and partially aromatic heterocyclic group containing at least one heteroatom selected from O, S and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1 -3 additional N atoms, with up to 5 heteroatoms being present;

n represents 2, 3 or 4;

each R² and R³ are selected from the group consisting of: H, Cualkyl, OH and NH2, with no more than one being OH or NH2; and

each R¹ is H or is selected from the group consisting of:

a) halo, OH and NH₂;

b) NR'S0₂R" wherein R' represents H, Ci_-3alkyl or haloCi_-3alkyl, and R" represents Hetcy, Aryl or HAR, said Aryl and HAR being further optionally substituted with 1 -3 halo,

groups; and

c) phenyl or a 5-6 membered heteroaryl or heterocyclic group attached at any available point and being optionally substituted with 1-3 halo, Ci alkyl or haloCi^alkyl groups, or 1 -2 OCualkyl or haloOCijalkyl groups, or 1 moiety selected from the group consisting of OH and N¾.

[0200] Examples of compounds of represented by Formula (XXI) are set forth in Figure 3.

[0201] In some embodiments of the present invention, a GP 109A agonist is compound 1 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0202] In some embodiments of the present invention, a GPR109A agonist is compound 2 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. [0203] In some embodiments of the present invention, a GPR109A agonist is compound 3 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0204] In some embodiments of the present invention, a GPR109A agonist is compound 4 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0205] In some embodiments of the present invention, a GPR109 A agonist is compound 5 as shown in Figure 3.

[0206] In some embodiments of the present invention, a GPR109A agonist is compound 6 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0207] In some embodiments of the present invention, a GPR109A agonist is compound 7 as shown in Figure 3. or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0208] In some embodiments of the present invention, a GPR109 A agonist is compound 8 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0209] In some embodiments of the present invention, a GPR109A agonist is compound 9 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0210] In some embodiments of the present invention, a GPR109A agonist is compound 10 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0211] In some embodiments of the present invention, a GPR109A agonist is compound 1 1 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0212] In some embodiments of the present invention, a GPR109 A agonist is compound 12 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. [0213] In some embodiments of the present invention, a GPR109A agonist is compound 13 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0214] In some embodiments of the present invention, a GPR109A agonist is compound 14 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0215] In some embodiments of the present invention, a GPR109A agonist is compound 15 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0216] In some embodiments of the present invention, a GPR109A agonist is compound 16 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0217] In some embodiments of the present invention, a GPR109A agonist is compound 17 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0218] ^' In some embodiments of the present , invention, a GPR109A agonist is compound 18 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0219] In some embodiments of the present invention, a GPR109A agonist is compound 19 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0220] In some embodiments of the present invention, a GPR109A agonist is compound 20 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0221] In some embodiments of the present invention, a GPR109A agonist is compound 21 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0222] In some embodiments of the present invention, a GPR109A agonist is compound 22 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. [0223] In some embodiments of the present invention, a GPR109 A agonist is compound 23 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0224] In some embodiments of the present invention, a GPR109A agonist is compound 24 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0225] In some embodiments of the present invention, a GPR109A agonist is compound 25 as shown in Figure 3 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0226] GPR109A agonists represented by Formula (XXI) may be prepared according to the methodology described in WO2008/051403.

[0227] In some embodiments of the present invention, a GPR 109A agonist is 3-( 1 H- tetrazol-5-yl)-l ,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354; Semple et al., 2008, J Med Chem 51 (16): 101 -8: incorporated herewith by reference in its entirety) as represented by Formula (XXII):

[0228] Semple et al. described 3-( 1 H-tetrazol-5-y 1)- 1 ,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354) for the treatment of dyslipidemia (2008, J Med Chem 51 ( 16):5101 -8). MK-0354 is an orally administered drug candidate under development by Merck for the treatment of atherosclerosis and related disorders. A Phase 1 clinical trial program of MK-0354 included two randomized, double-blind, placebo-controlled studies evaluating the safety, tolerability and pharmacokinetics of MK-0354 in healthy volunteers. In both studies MK-0354 was generally well-tolerated at all doses studied. Semple et al. did not suggest to use 3-(l H- tetrazol-5-yl)-l ,4,5,6-tetrahydro-cyclopentapyrazole in a method to treat, prevent, or alleviate an ischemic condition. [0229] In some embodiments of the present invention, a GPR109A agonist is 1 ,4,5,6- Tetrahydro-cyclopenta[c]pyrazole-3-carboxylic acid (Semple et al, 2008, J Med Chem

51 (16):5101 -8: incorporated herewith by reference in its entirety) as represented by Formula (XXIII):

[0230] In some embodiments of the present invention, a GPR109A agonist is 6-Methyl- l ,4,5,6-tetrahydro-cyclopenta[c]pyrazole-3-carboxylic acid (Semple et al, 2008, J Med Chem 51(16):5101 -8: incorporated herewith by reference in its entirety) as represented by Formula (XXIV):

[0231] Pyrazole GPR109A agonists for use in the methods of the present invention, e.g., are also described in Richman et al. (2007, J Biol Chem 282(5): 18028-26) and in van Herk et al. (2003, J Med Chem 46:3945-3951 ; incorporated herewith by reference in their entirety). Neither Richman et al. nor van Henk et al. suggested to use a pyrazole GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0232] In some embodiments of the present invention, a GPR109 A agonist is a pyrazole agonist corresponding to structure l a of Richman et al. (2007 ^', J Biol Chem 282(5): 1 8028-26) as represented by Formula (XXV):

[0233] The compound of Formula (XXV) is also described as 5-(3-chlorobenzyl)- l H- pyrazole-3-carboxylic acid or 5-meta-chlorobenzyl-3-carboxyl-pyrazole.

[0234] In some embodiments of the present invention, a GPR 109A agonist is a pyrazole agonist corresponding to structure 1 b of Richman et al. (2007, J Biol Chem 282(5): 1 8028-26) and represented by Formula (XXVI):

[0235] The compound of Formula (XXVI) is also described as 5-(3-bromobenzyl)- l H- pyrazole-3-carboxylic acid or 5-meta-bromobenzyl-3-carboxyl-pyrazole.

[0236] In some embodiments of the present invention, a GPR 109A agonist is a pyrazole agonist corresponding to structure 1 c of Richman et al. (2007, J Biol Chem 282(5): 1 8028-26) and represented by Formula (XXVII):

[0237] The compound of Formula (XXVII) is also described as 5-(3-fluorobenzyl)- 1 H- pyrazole-3-carboxylic acid or 5-meta-fluorobenzyl-3carboxyl-pyrazole. [0238) In some embodiments of the present invention, a GPR109A agonist is a pyrazole agonist corresponding to structure 2a of Richman et al. (2007, J Biol Chem 282(5): 1 8028-26) and represented by Formula (XXVIII):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof

[0239] The compound of Formula (XXVIII) is also described as 5-isopropyl-l H-pyrazole- 3-carboxylic acid or 5-isopropyl-3-carboxyl-pyrazoIe.

[0240J In some embodiments of the present invention, a GPR109A agonist is a pyrazole agonist corresponding to structure 3a of Richman et al. (2007 , J Biol Chem 282(5): 1 8028-26) and represented by Formula (XXIX):

[0241] The compound of Formula (XXIX) is also described as 5-methyl-l H-pyrazole-3- carboxylic acid or 5-methyl-3-carboxyl-pyrazole.

[0242] In some embodiments of the present invention, a GPR109A agonist is a pyrazole agonist corresponding to structure 4a of Richman et al. (2007, J Biol Chem 282(5): 18028-26) as represented by Formula (XXX):

[0243] The compound of Formula (XXX) is also described as 3-methylisoxazole-5- carboxylic acid or 3-methyl-5-carboxyl isoxazole. [0244] Further, substituted pyrazole-3-carbox lic acids that proved to have substantial affinity for GPR109A and which can be used in the methods of the present invention are described by van Herk et al. (2003, J Med Chem 46:3945-3951 ; incorporated by reference in its entirety). In some embodiments, a GPR109A agonist is a substituted pyrazole-3- carboxylic acids represented by Formula (XXXI):

Ri is— CH₂CH₂O— ,— C3H6— ,— C4H8— , -C3H7,— C3H7,— C4H9,— Ci 1H23,— C₆H₅, 3-Cl-C₆H4, 4-CI-C6H4, 4-CH₃-C₆H4, C₆H₅-CH₂, 4-Cl-C₆H4-CH₂, 4-CH3-C₆H4-CH₂, 4- OCH3-C₆H4-CH₂, 3-Cl-C₆H4-CH₂, CeHs- -FL,, or C₆H5-C₃H6; and

R₂ is H.

[0245] Affinities of these compounds were measured by inhibition of [³H]nicotinic acid binding to rat spleen membranes. Potencies and intrinsic activities relative to nicotinic acid were determined by their effects on [³⁵S]GTPyS binding to rat adipocyte and spleen membranes.

|0246] In particular, l ,2-Diaza-bicyclo[3,3,0 '⁸]octa-3,8-diene-3-carboxylic acid (Formula (XXXII), compound 4(c) in van Herk et al. (2003 , J Med Chem 46:3945-3951 ) and 5-propyl- l H-pyrazole-3-carboxylic acid (Formula (XXXIII)) compound (4f) in van Herk et al. (2003, J Med Chem 46:3945-3951) proved active with Kj values of approximately 0.15 μΜ and EC50 values of approximately 6 μΜ, while their intrinsic activity was only approximately 50% when compared to nicotinic acid. Even slightly more active was 5-butyl-lH-pyrazole-3- carboxylic acid (Formula (XXXFV), compound (4g) in van Herk et al. (2003, J Med Chem 46:3945-3951 ) with a j value of 0.072 μΜ, an EC₅₀ value of 4.12 μΜ, and a relative intrinsic activity of 75%.

[0247] In some embodiments of the present invention, a GPR 109 A agonist is a pyrazole agonist represented by Formula (XXXII):

[0248] In some embodiments of the present invention, a GPR109A agonist is a pyrazole agonist represented by Formula (XXXIII):

[0249] In some embodiments of the present invention, a GPR109A agonist is a pyrazole agonist represented by Formula (XXXIV):

[0250] van Herk et al, (2003, J Med Chem 46:3945-3951 ) also described aralkyl derivatives useful for methods of the present invention. Of those, 5-(3- chlorobenzyl)pyrazole-3-carboxylic acid (Formula (XXXV)) compound (4q) in van Herk et al. (2003, J Med Chem 46:3945-3951 ) was the most active with a relatively low intrinsic activity of 39%.

[0251] In some embodiments of the present invention, a GPR109A agonist is a pyrazole agonist represented by Formula (XXXV):

[0252] In some embodiments of the present invention, a GPR109A agonist is a C5- substituted pyrazole-tetrazole GPR109A agonist, such as a 5-alkyl or aryl-pyrazole-tetrazole GPR109A agonist, as described by Imbriglio et al. (2009, Bioorg Med Chem Lett 19(8):2121 - 4; incorporated herewith by reference in its entirety).

[0253] In some embodiments of the present invention, a GPR109A agonist is a C5- substituted pyrazole-tetrazole GPR109A agonist represented by Formula (XXXVI):

Ri is H, ethyl, w-propyl, Λ-butyl, e«/-n-butyl, w-pentane, w-hexane, cyclopropyl, cyclopentyl, Ph, 3-Me-Ph, 2-Me-Ph, 4-Cl-Ph, 4-F-Ph, 2,4-F-Ph, 2,5-F-Ph, 2-Cl-Ph, 3,4-F-Ph, 2,3-F-Ph, 2-F-Ph, 3-Cl-Ph, 3-F-Ph, 2,3,5-F-Ph, ent 2,3,5-F-Ph, or 3,5-F-Ph, and

R₂ is tetrazole.

[0254] Imbriglio et al. did not suggest to use a C5-substituted pyrazole-tetrazole GPR109A agonist, such as a 5-alkyl or aryl-pyrazole-tetrazole GPR109A agonist, in a method to treat, prevent, or alleviate an ischemic condition.

[0255] In some embodiments of the present invention, a GPR109 A agonist is a 4,5- disubstituted pyrazole-3-carboxylic acid GPR109A agonist as described by Skinner et al. (2007, Bioorg Med Chem Lett 17(20):5620-3; incorporated herewith by reference in its entirety)

[0256] In some embodiments of the present invention, a GPR 109A agonist is a 4,5- disubstituted pyrazole-3-carboxylic acid GPR109A agonist represented by Formula

(XXXVII):

Ri is H, methyl, ethyl, propyl, /-propyl, c-propyl, butyl, c-butyl, pentyl, and

R.2 is H, methyl, or halogen.

[0257] Skinner et al. did not suggest to use a 4,5-disubstituted pyrazole-3-carboxylic acid GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0258] In some embodiments of the present invention, a GPR109A agonist is a 4,5- disubstituted pyrazole-3-tetrazole GPR109A agonist as described by Skinner et al. (2007, Bioorg Med Chem Lett 17(20):5620-3; incorporated herewith by reference in its entirety)

[0259] In some embodiments of the present invention, a GPR109 A agonist is a 4,5- disubstituted pyrazole-3-tetrazole GPR109A agonist represented by Formula (XXXVIII):

Ri is H, methyl, ethyl, propyl, /-propyl, c-propyl, butyl, and

R₂ is H or halogen.

[0260] Skinner et al. did not suggest to use a 4,5-disubstituted pyrazole-3-tetrazole GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0261] In some embodiments of the present invention, a GPR109A agonist is a GPR109A agonist as described by Boatman et al. (2008, J Med Chem 51 (24):7653-62; incorporated herewith by reference in its entirety). [0262] In some embodiments of the present invention, a GPR109A agonist is a pyrazole-3- carboxylic acid GPR109A agonist (compound 3 of Boatman et al.) represented by Formula (XXXIX):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, wherein n is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 1 3, or 14.

[0263] In some embodiments of the present invention, a GPR109A agonist is a pyrazole-3- carboxylic acid GPR 109A agonist (compound 4 of Boatman et al.) represented by Formula (XXXX):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, wherein X is a branched alkyl, phenyl or benzyl.

[0264] In some embodiments of the present invention, a GPR109 A agonist is a pyrazole-3 carboxylic acid GPR 109A agonist (compound 5 of Boatman et al.) represented by Formula (XXXXI):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, wherein X is CH₂, CH₂CH₂ or O.

[0265] In some embodiments of the present invention, a GPR109A agonist is a pyrazolecarboxylic acid GPR109A agonist (compound 15 of Boatman et al.) represented by Formula (XXXXII):

[0266] In some embodiments of the present invention, a GPR109A agonist is a pyrazolecarboxylic acid GPR109A agonist (compound 16 of Boatman et al. ) represented by Formula (XXXXIII):

[0267] In some embodiments of the present invention, a GPR109A agonist is selected from the group consisting of compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 1 1 , compound 12 as shown in Figure 4A, and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

[0268] Gharbaoui et al. did not suggest to use a urea a 6-membered heterocyclic acid GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0269] In some embodiments of the present invention, a GPR 109A agonist is a 5- substituted pyrazole acid GPR 109A agonist.

[0270] In some embodiments of the present invention, a GPR 109A agonist is a 5- substituted pyrazole acid GPR 109A agonist as described by Gharbaoui et al. (2007, Bioorg Med Chem Lett 17( 1 7):4914-9; incorporated herewith by reference in its entirety) and as shown in Figure 4C or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0271 J In some embodiments of the present invention, a GPR 109A agonist is selected from the group consisting of compound 13, compound 22, compound 23, compound 24, compound 25, compound 26, compound 27, compound 28, compound 29, compound 30, compound 31 , compound 32, compound 33, compound 34, compound 35, compound 36, compound 37, compound 38, compound 39, compound 40, compound 41 , compound 42, compound 43, compound 44, compound 45, compound 46 as shown in Figure 4C, and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

[0272] Gharbaoui et al. did not suggest to use a urea a 5-substituted pyrazole acid

GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0273] In some embodiments of the present invention, a GPR109A agonist is a bicyclic pyrazole acid GPR109A agonist.

[0274] In some embodiments of the present invention, a GPR109A agonist is a bicyclic pyrazole acid GPR109A agonist as described by Gharbaoui et al. (2007, Bioorg Med Chem Lett 17(17):4914-9; incorporated herewith by reference in its entirety) and as shown in Figure 4D or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0275] In some embodiments of the present invention, a GPR109A agonist is selected from the group consisting of compound 47, compound 48, compound 49, compound 50, compound 51 , compound 52, compound 53, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 60, compound 61 , compound 62, compound 63, compound 64, compound 65, compound 66, compound 67 as shown in Figure 4D, and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

[0276] Gharbaoui et al. did not suggest to use a urea a bicyclic pyrazole acid GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

9. Pyrazolopyrimidine GPR109A Agonists

[0277] In some embodiments of the present invention, a GPR109A agonist is a pyrazolopyrimidine GPR109A agonist

[0278] In some embodiments of the present invention, a GPR109A agonist is a pyrazolopyrimidine GPR109A agonist as described by Shen et al. (2008, Bioorg Med Chem Lett 18(18):4948-51 ; incorporated herewith by reference in its entirety) and as shown in Figure 5 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0279] In some embodiments of the present invention, a GPR109A agonist is selected from the group consisting of compound 9a, compound 9b, compound 9c, compound 9d, compound 9e compound 9f, compound 9g, compound 9h, compound 9i, compound 9j, compound 9k, compound 91, compound 9m, compound 9n, compound 9o, compound 9p, compound 9q as shown in Figure 5, and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

[0280] In some embodiments, a pyrazolopyrimidine GPR109A is compound 9n or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof (Figure 5).

[0281] Shen et al. did not suggest to use a pyrazolopyrimidine GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

10. Pyridopyrimidinone GPR109A Agonists

[0282] In some embodiments, of the present invention a GPR109A agonist is a

Pyridopyrimidinone GPR109A agonist as set forth herein. Pyridopyrimidinone GPR109A agonists useful for practicing methods of the present invention are described , e.g., in US2007/025987; incorporated herewith by reference in its entirety).

[0283] In some embodiments of the present invention, a GPR109A agonist is a compound represented by Formula (XXXXIV):

Y

R⁸ or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, wherein;

X is selected from the group consisting of: a single bond, O, N(R⁹)C(0),

R , R , and R are independently from each other selected from the group consisting of: hydrogen, halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, and cycloalkyl;

R⁴, R⁵, R⁶ and R⁷ are independently from each other selected from the group consisting of: hydrogen, fluoro, lower-alkyl, and fluoro-lower-alkyl; or alternatively, R⁴ and R⁵ are bound together to form a ring together with the carbon atom to which they are attached wherein— R— R⁵— is— (CH₂)2-6— , or R⁶ and R⁷ are bound together to form a ring together with the carbon atom to which they are attached wherein— R⁶— R⁷— is— (CH₂)₂_6— ;

R⁸ is aryl is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently from each other selected from the group consisting of: halogen, lower-alkyl, lower-alkoxy, fluoro-lower-alkyl, fluoro-lower-alkoxy, cycloalkyl, fluoro-cycloalkyl, cycloalkyl-oxy, C(0)OH, lower-alkoxy-C(O), NH₂C(0), N(H,Iower-alkyl)C(0), N(lower-alkyl)₂C(0), OH, lower-alkyl-C(0)0, NH₂, N(H,lower- alkyl), N(lower-alkyl)₂, lower-alkyl-C(0)NH, lower-alkyl-C(0)N(lower-alkyl), NH₂S0₂, N(H,lower-alkyl)S0₂, N(lower-alkyl)₂S0₂, lower-alkyl-SC>2— NH, lower-alkyl-SCV- N(lower-alkyl), cyano, and phenyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, lower-alkyl, lower-alkoxy and fluoro-lower-alkyl;

m is 0, 1 , 2 or 3; and n is 0, 1 , 2, 3, 4, 5 or 6; wherein m+n is >1 .

[0284] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein X is selected from the group consisting of: a single bond, O, N(R⁹)C(0), N(R⁹)C(0)0, OC(0)NR⁹, N(R⁹)C(0)NR¹⁰, and C(0)NR⁹ if m is 1 , 2, or 3 and Y is selected from the group consisting of: a single bond, and O if n is 1 , 2, 3, 4, 5, or 6. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0285] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein X is selected from the group consisting of: a single bond, O, N(R⁹)C(0), N(R⁹)C(0)0, N(R⁹)C(0)NR¹⁰ Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0286] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein X is selected from the group consisting of: a single bond, O, N(R⁹)C(0), N(R⁹)C(0)0. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0287] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein X is N(R⁹)SC>2. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0288] In some embodiments of the present invention, a GPR 109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein the X groups are bound to the (CR⁴R⁵)_m group on their left side and to the (CR⁶R⁷)„ group on their right side. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0289] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R¹, R² and R³ independently from each other are selected from the group consisting of hydrogen, halogen, lower-alkyl and cycloalkyl. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0290] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R¹, R² and R³ independently from each other are selected from the group consisting of hydrogen, halogen and lower-alkyl. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV). [0291] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R¹ is hydrogen, methyl, or fluoro. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0292] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R¹ is hydrogen or methyl. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0293] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R² is hydrogen, methyl, ethyl, butyl, fluoro, chloro or bromo. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0294] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXrV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R² is hydrogen, methyl or bromo. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0295] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXrV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R³ is hydrogen. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0296] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R⁴, R⁵, R⁶ and R⁷ independently from each other are hydrogen or lower-alkyl. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0297] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R⁴, R^s, R⁶ and R⁷ are hydrogen. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0298] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein m or n are larger than 1 . In these embodiments, more than one of R⁴, R^s, R⁶ and R⁷ can occur. In these embodiments, R⁴, R⁵, R⁶ and R⁷ can be the same or different. For example, if m is 3 and R⁴ and R^s are hydrogen or lower-alkyl, the group— (CR R⁵)3— can, for example, be— CH(CH₃)— CF— CH2— . Furthermore, in embodiments wherein m or n are larger than 1 , it is preferred that only one R⁴ and R^s or one R⁶ and R⁷ are bound together to form a cycloalkyl. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0299] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R⁸ is aryl or heteroaryl, which aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, lower-alkyl, lower-alkoxy, fluoro-lower-alkyl, fluoro-lower-alkoxy, and phenyl which is optionally substituted halogen. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0300] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R⁸ is aryl or heteroaryl, which aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, lower-alkyl, lower-alkoxy or fluoro-lower-alkyl. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0301] In some embodiments of the present invention, a GPR109A agonist of Formula . (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R⁸ is phenyl or naphthyl, which phenyl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of halogen and lower-alkoxy. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0302] In some embodiments of the present invention, a GPR109 A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R⁸ is phenyl, 4-fluoro-phenyl, 3-chloro-phenyl, 2-methoxy- phenyl, 2-chloro-phenyl, 2-fluoro-phenyl, 3,4-dichloro-phenyl, naphthalen- l -yl, or naphthalen-2-yl. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV). [0303] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXrV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R⁸ is 3-chloro-4-fluoro-phenyl, 2,5-difluoro-phenyl or 5- methyl-2-phenyl-oxazol-4-yl. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0304] In some embodiments of the present invention, a GPR109 A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein m is 0 or 1. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0305] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein n is 0, 1 , 2, 3, or 4. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0306] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R⁹ and R¹⁰ are hydrogen. Within these embodiments, all other variables are as set forth with respect to Formula (XXXXIV).

[0307] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) is selected from the group consisting of 2-Benzyloxymethyl-3H-pyrido[2,3- d]pyrimidin-4-one, 2-Phenoxymethyl-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(4-ChIoro- phenoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(5-Phenyl-pentyl)-3H-pyrido[2,3- d]pyrimidin-4-one, 2-(4-Methoxy-phenoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(4- Ethyl-phenoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(4-Phenyl-butyl)-3H-pyrido[2,3- d]pyrimidin-4-one, 2-(4-Fluoro-phenoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(3- Chloro-phenoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-Phenethyl-3H-pyrido[2,3- d]pyrimidin-4-one, 2-[2-(3-Chloro-phenyl)-ethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(3- Methoxy-phenyl)-ethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[4-(4-Chloro-phenyl)-butyl]- 3H-pyrido[2,3-d]pyrimidin-4-one, 2-(6-Phenyl-hexyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2- [4-(4-Fluoro-phenyl)-butyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(2-Methoxy- phenoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-p-Tolyloxymethyl-3H-pyrido[2,3- d]pyrimidin-4-one, 2-(2-Chloro-phenoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(2,3- Dimethyl-phenoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(Naphthalen- l - yloxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(4-Chloro-2-methyl-phenoxymethyl)-3H- pyrido[2,3-d]pyrimidin-4-one, 6-Methyl-2-(4-phenyl-butyl)-3H-pyrido[2,3-d]pyrimidin-4- one, (4-Oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-carbamic acid benzyl ester, N- (4-Oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-3-phenyl-propionamide, N-(4-Oxo- 3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-4-phenyl-bu-tyramide, 6-Bromo-2-(4- phenyl-butyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Bromo-2-[4-(4-fluoro-phenyl)-butyl]-3H- pyrido[2,3-d]pyrimidin-4-one, 2-[3-(4-Methoxy-phenyl)-propoxy]-3H-pyrido[2,3- d]pyrimidin-4-one, 2-(3-Phenyl-propoxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(4-Phenyl- butoxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[4-(4- ethoxy-phenyl)-butoxy]-3H-pyrido[2,3- d]pyrimidin-4-one, 2-(3-Pyridin-3-yl-propoxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(2- Phenoxy-ethoxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(Naphthalen-2-yloxy)-ethoxy]-3H- pyrido[2,3-d]pyrimidin-4-one, 2-(3-Phenoxy-propoxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 2- Phenethyloxymethyl-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(2-Fluoro-phenyl)- ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[3-(3,4-Difluoro-phenoxy)-propoxy]-3H- pyrido[2,3-d]pyrimidin-4-one, 2-[3-(4-Methoxy-phenoxy)-propoxy]-3H-pyrido[2,3- d]pyrimidin-4-one, 2-[2-(4-Fluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[4-(4-Fluoro-phenyl)-3-methyl-butyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[5-(4-Chloro- phenyl)-pentyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[3-(4-Fluoro-phenoxy)-propyl]-3H- pyrido[2,3-d]pyrimidin-4-one, 2-[2-(4-Chloro-phenyl)-ethoxymethyl]-3H-pyrido[2,3- d]pyrimidin-4-one, 2-(2-p-Tolyl-ethoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(4- Methoxy-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(2-Benzyloxy-ethyl)- 3H-pyrido[2,3-d]pyrimidin-4-one, 2-(4'-Fluoro-biphenyl-4-yloxymethyl)-3H-pyrido[2,3- d]pyrimidin-4-one, 2-(4-m-Tolyl-butyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(l -Methyl-4- phenyl-butyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(Naphthalen-2-yloxymethyl)-3H- pyrido[2,3-d]pyrimidin-4-one, l -Benzyl-3-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2- ylmethyl)-urea, 2-[2-(4-Fluoro-phenyl)-ethoxymethyl]-6-methyl-3H-pyrido[2,3-d]pyrimidin- 4-one, 2-(4-Iodo-phenoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[3-(4-Fluoro- phenoxy)-propoxy]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(3-p-Tolyloxy-propoxy)-3H- pyrido[2,3-d]pyrimidin-4-one, 2-[3-(2-Fluoro-phenoxy)-propoxy]-3H-pyrido[2,3- d]pyrimidin-4-one, 2-(3-o-Tolyloxy-propoxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(2- Fluoro-phenyl)-ethoxymethyl]-7-methyl-3H-pyrido[2,3-d]pyrimidin-4-one, (4-Oxo-3,4- dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-carbamic acid 2-chloro-benzyl ester, 2-[3-(3- Fluoro-phenoxy)-propoxy]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(3-m-Tolyloxy-propoxy)- 3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(2-Trifluoromethyl-phenyl)-ethoxymethyl]-3H- pyrido[2,3-d]pyrimidin-4-one, 2-[2-(2-Methoxy-phenyl)-ethoxymethyl]-3H-pyrido[2,3- d]pyrimidin-4-one, 2-(2-o-Tolyl-ethoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(2- Chloro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-Phenethyloxy-3H- pyrido[2,3-d]pyrimidin-4-one, 2-(3,4-Dichloro-benzyloxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(4-Fluoro-phenyl)-ethoxy]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(2,4-Difluoro- benzyloxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(4-Chloro-phenyl)-ethoxy]-3H- pyrido[2,3_rd]pyrimidin-4-one, 2-(5-Phenyl-pentyloxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 2- (6-Phenyl-hexyloxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[3-(4-Chloro-phenoxy)-propoxy]- 3H-pyrido[2,3-d]pyrimidin-4-one, 2-[3-(2-Chloro-phenoxy)-propoxy]-3H-pyrido[2,3- d]pyrimidin-4-one, 2-[2-(3-Chloro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Methyl-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrirnidin-2-ylmethyl)-carbarnic acid benzyl ester and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

[0308] In some embodiments of the present invention, a GPR109 A agonist of Formula (XXXXIV) is selected from the group consisting of 2-[4-(4-Fluoro-phenyl)-butyl]-3H- pyrido[2,3-d]pyrimidin-4-one, 2-(2-Methoxy-phenoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4- one, 2-(Naphthalen-l -yloxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 6- ethyl-2-(4- phenyl-butyl)-3H-pyrido[2,3-d]pyrimidin-4-one, (4-Oxo-3,4-dihydro-pyrido[2,3- d]pyrimidin-2-ylmethyl)-carbamic acid benzyl ester, N-(4-Oxo-3,4-dihydro-pyrido[2,3- d]pyrimidin-2-ylmethyl)-3-phenyl-propionamide, 2-[2-(Naphthalen-2-yloxy)-ethoxy]-3H- pyrido[2,3-d]pyrimidin-4-one, 2-(3-Phenoxy-propoxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 2- [2-(2-Fluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(Naphthalen-2- yloxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(2-Fluoro-phenyl)-ethoxymethyl]-7- methyl-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(3,4-Dichloro-benzyloxy)-3H-pyrido[2,3- d]pyrimidin-4-one, 2-[3-(2-Chloro-phenoxy)-propoxy]-3H-pyrido[2,3-d]pyrimidin-4-one, 2- [2-(3-Chloro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

[0309] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) is selected from the group consisting of 6-Chloro-2-[2-(2,5-difluoro-phenyl)- ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Chloro-2-[2-(3-chloro-phenyl)- ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Chloro-2-[2-(4-fluoro-phenyl)- ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Chloro-2-[2-(3-trifluoromethoxy- phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Chloro-2-[2-(3-chloro-4-fluoro- phenyl)-ethoxymethyl]-3H-pyrido[2,- 3-d]pyrimidin-4-one, 6-Chloro-2-[2-(4-chloro-phenyl)- ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 3-(3-Fluoro-phenyl)-N-(4-oxo-3,4-dihydro- pyrido[2,3-d]pyrimidin-2-ylmethyl)-propionamide, 2-[2-(3-Chloro-phenyl)-ethoxymethyl]-6- fluoro-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(3-Chloro-phenyl)-ethoxymethyl]-7-fluoro- 3H-pyrido[2,3-d]pyrimidin-4-one, 2-(5-Methyl-2-phenyl-oxazol-4-yl)-N-(4-oxo-3,4-dihydro- pyrido[2,3-d- ]pyrimidin-2-ylmethyl)-acetamide, 2-[l ,2,4]Triazol-l -ylmethyl-3H-pyrido[2,3- d]pyrimidin-4-one, 2-(3-Chloro-phenoxy)-N-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2- ylmethyl)-acetamide, N-(4-Oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-2-(pyridin- 2-yloxy)-acetamide, 2-[2-(3-Fluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4- one, 2-[2-(3-Methoxy-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 7-Fluoro-2- [4-(4-fluoro-phenyl)-butyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 7-Fluoro-2-[2-(2-fluoro- phenyl)-ethoxymethyl]-3H-pyrido[2,- 3-d]pyrimidin-4-one, N-(6-Fluoro-4-oxo-3,4-dihydro- pyrido[2,3-d]pyrimidin-2-ylmethyl)-3~ phenyl-propionamide, 7-Fluoro-2-[2-(3- trifluoromethyl-phenyl)-ethoxymethyl]-3H pyrido[2,- 3-d]pyrimidin-4-one, 5-Methyl-2-(5- phenyl-pentyloxy)-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Chloro-2-(3-phenoxy-propoxy)-3H- pyrido[2,3-d]pyrimidin-4-one, 7-Methyl-2-(5-phenyl-pentyloxy)-3H-pyrido[2,3-d]pyrimidin- 4-one, 2-[3-(2-Chloro-phenoxy)-propoxy]-5-methyl-3H-pyrido[2,3-d]pyrimidin-4-one, 7- Fluoro-2-[2-(3-fluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3~ d]pyrimidin-4-one, 7-Fluoro- 2-[2-(4-fluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 3-(2-Chloro- phenyl)-N-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-propionamide, 3-(3- Chloro-phenyl)-N-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-propionarnide, 2- [2-(2-Chloro-phenyl)-ethoxymethyl]-7-fluoro-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Chloro-2- [2-(2-chloro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Fluoro-2-[2-(3- fluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Chloro-2-[4-(4-fluoro- phenyl)-butyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(2-Chloro-6-fluoro-phenyl)- ethoxymethyl]-7-fluoro-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(2-m-Tolyl-ethoxymethyl)-3H- pyrido[2,3-d]pyrimidin-4-one, 2-[2-(4-Chloro-phenyl)-ethoxymethyl]-7-fluoro-3H- pyrido[2,3-d]pyrimidin-4-one, 3-(4-Chloro-phenyl)-N-(4-oxo-3,4-dihydro-pyrido[2,3- d]pyrimidin-2-ylmethyl)-propionamide, (6-Fluoro-4-oxo-3,4-dihydro-pyrido[2,3- d]pyrimidin-2-ylmethyl)-carbamic acid benzyl ester, 2-[2-(2,5-Difluoro-phenyl)- ethoxymethyl]-7-fluoro-3H-pyrido[2,3-d]pyrimidin-4-one, N-(4-Oxo-3,4-dihydro-pyrido[2,3- d]pyrimidin-2-ylmethyl)-3-m-tolyl-propionamide, 7-Fluoro-2-[2-(3-trifluoromethoxy- phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 3-(3-Methoxy-phenyl)-N-(4-oxo- 3,4-dihydro-pyrido[2,3-d]pyrirnidin-2-ylmethyl)-propionamide, 2-[2-(3-Chloro-4-fluoro- phenyl)-ethoxymethyl]-7-fluoro-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(2,5-Difluoro- phenyl)-ethoxymethyl]-6-fluoro-3H-pyrido[2,3-d]pyrimidin-4-one, (6-Chloro-4-oxo-3,4- dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-carbamic acid benzyl ester, (7-Chloro-4-oxo- 3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-carbamic acid benzyl ester, (7-Fluoro-4- oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-carbamic acid benzyl ester, 6-Chloro-2- (2-naphthalen-2-yl-ethoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(2,5-Difluoro- phenyl)-ethoxymethyl]-6-ethyl-3H-pyrido- [2,3-d]pyrimidin-4-one, 2-[2-(3-Chloro-phenyl)- ethoxymethyl]-6-ethyl-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Butyl-2-[2-(3-chloro-phenyl)- ethoxymethyl]-3H-pyrido[2,- 3-d]pyrimidin-4-one, 6-Butyl-2-[2-(2,5-difluoro-phenyl)- ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(3-Chloro-4-fluoro-phenyl)- ethoxymethyl]-6-ethyl-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Cyclopropyl-2-(4-phenyl-butyl)- 3H-pyrido[2,3-d]pyrimidin-4-one, 2-(2-Fluoro-phenyl)-ethanesulfonic acid (4-oxo-3,4- dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-amide, 2-(3-Chloro-phenyl)-ethanesulfonic acid (4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-amide, and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

[0310] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXIV) is selected from the group consisting of 6-Chloro-2-[2-(3-chloro-4-fluoro- phenyl)-ethoxymethyl]-3H-pyrido[2,- 3-d]pyrimidin-4-one, 2-[2-(3-Chloro-phenyl)- ethoxymethyl]-6-fluoro-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(3-Chloro-phenyl)- ethoxymethyl]-7-fluoro-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(5-Methyl-2-phenyI-oxazol-4- yl)-N-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-acetamide, 6-Chloro-2-(3- phenoxy-propoxy)-3H-pyrido[2,3-d]pyrimidin-4-one, (6-Fluoro-4-oxo-3,4-dihydro- pyrido[2,3-d]pyrimidin-2-ylmethyl)-carbamic acid benzyl ester, 2-[2-(2,5-Difluoro-phenyl)- ethoxymethyl]-6-fluoro-3H-pyrido[2,3-d]pyrimidin-4-one, 2-[2-(2,5-Difluoro-phenyl)- ethoxymethyl]-6-ethyl-3H-pyrido[2,3-d]pyrimidin-4-one, 6-Butyl-2-[2-(2,5-difluoro-phenyl)- ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one, 2-(2-Fluoro-phenyl)-ethanesulfonic acid (4-0X0-3 ,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-amide, and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

[0311] GPR109A agonists represented by Formula (XXXXIV) may be prepared according to the methodology described in US2007/0275987.

11. Anthranilic Acid GPR109A Agonists

[0312] In some embodiments, of the present invention a GPR109A agonist is an anthranilic acid GPR109A agonist as set forth herein. Anthranilic acid GPR109A agonists useful for practicing methods of the present invention are described , e.g., in US2008/0221 108 and in Shen and Colletti, 2009, Expert Opin Ther Pat 19(7):957-67; each; incorporated herewith by reference in its entirety). [0313] In some embodiments of the present invention, A GPR 109A agonist is a compound represented by Formula (XXXXV):

R¹ represents hydrogen, halogen or C|-C₃alkyl;

R² represents a 6 or 10-member aryl or heteroaryl ring system;

W represents a linker selected from:— C(R³R⁴)— (CH₂)„— ,

— C(R³R⁴)— (CH₂)„NHC(0>— ,— C(R³R⁴)— (CH₂)„NHC(0)NH— ,

— C(R³R⁴)— (CH₂)_nNHC(0)0— ,— C(R³R⁴)— (CH₂)„S0₂NR5³— ,

- (R³R⁴)— (CH₂)„NR⁵S0₂— ,— C(R³R⁴)— (CH₂)„0— ,— C(R³R⁴)— <CH₂)„C(0)— , — C(R³R⁴)— (CH₂)„NH— ,— C(R³R⁴)— (CH₂)„S— ,— C(R³R⁴)— (CH₂)„0— CHj— ,

V represents CH or N; X, Y and Z independently represent CH, O, N or S, with the proviso that all three of

X, Y and Z may not represent CH;

A represents a linker selected from:— C(R³R⁴)— (CH₂)„—— C(R^JR'¹)— (CH₂)_nO— , — C(R³R⁴)— (CH₂)„NH— , or— C(R³R⁴)— (CH₂)„S— ; n represents an integer selected from 0, 1 and 2;

R represents hydrogen, Ci-C₅alkyl, C₂-C₅alkenyl, C₅-C₆aryl or C5-C₆cycloalkyl; R⁴ represents, Ci-Csalkyl, C₂-Csalkenyl, Cs-Cearyl or C₅-C₆cycloalkyI or R³ and R⁴ together with the carbon atom to which they are attached form a 4, 5, 6 or 7-member cycloalkyl ring; and

R⁵ represents hydrogen or C|-C₃alkyl.

[0314] In some embodiments of the present invention, a GPRl 09 A agonist of Formula (XXXXV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R¹ represents hydrogen, fluorine or methyl (e.g. hydrogen).

[0315] In some embodiments of the present invention, a GPRl 09A agonist of Formula (XXXXV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein W represents— C(R³R⁴)— (CH₂)„0— (e.g.— CH(CH₃)— O— ), — C(R³R⁴)— (CH₂)— (e.g.— CH(CH₃)— C¾— ),— C(R³R⁴)— (CH₂)„S—

(e.g. -CH(CH₃)— S— ),— C(R³R⁴)— (CH₂)„0— CH₂— (e.g.— CH(CH₃)0— CH;>— ), or

[0316] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein one of R³ and R⁴ represents hydrogen and the other represents Ci-C₂alkyl,

[0317] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein n represents 1 .

[0318] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R⁵ represents hydrogen or methyl. [0319] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R² represents an aryl, heteroaryl, biaryl, hetero-biaryl, fused aryl-cycloalkyl, fused heteroaryl-cycloalkyl, fused aryl-heterbcycle or fused heteroaryl- heterocyclic ring system, as herein defined.

[0320] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R² includes heteroatoms and wherein 1 to 3 heteroatoms are present. The R² ring system may be joined to the Z linker unit via either a ring carbon atom or via a heteroatom, where present.

[0321] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein the R² unit is a 10-member ring system. This is may be naphthyl or may have 1, 2 or 3 heteroatoms. Where 2 or 3 heteroatoms are present, some embodiments will have them all in the same ring of the fused system. In some embodiments of the present invention, the heteroatoms in a 10-member ring system are nitrogen atoms. In other embodiments of the present invention a 10-member R² group is selected from the group consisting of:

[0322] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein the R² unit is an unsubsituted 10-member ring system. I other embodiments of the present invention, in which R² is a substituted 10-member ring system, the substituents are selected from Ci-C2alkyl, (e.g. methyl),— C(0)Me, =0 and Ci- Csalkoxy (e.g. methoxy).

[0323] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein R² represents a 6 member heteroaryl ring, R² may be selected from thiophenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl. In other embodiments of the present invention, R² represents 6 member aryl, for example, phenyl. In some embodiments of the present invention, a GPR1 09 A agonist of Formula (bb) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein the R² unit represents an unsubstituted 6 member aryl or heteroaryl ring. Inother embodiments, wherein R² represents phenyl, this may be unsubstituted or may be singly substituted with methyl or with unsubstituted phenyl (i.e. may be methylphenyl or biphenyl).

[0324] In some embodiments of the present invention, a GPR109A agonist of Formula (XXXXV) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, is one wherein the R² ring is a substituted 6 member heteroaryl, and wherein the one or more substituents are selected from halogen (e.g. fluorine), Ci-C₃alk l (e.g. methyl), Ci-C₃alkoxy (e.g. methoxy), perfluoroC|-C₃alkyl (e.g. trifiuoromethyl), unsubstituted C6 aryl (phenyl),— NH— S0₂R³, C0₂H; and C0₂Me.

(0325] GPR109 A agonists represented by Formula (XXXXV) may be prepared according to the methodology described in US2008/0221 108.

[0326] In some embodiments of the present invention, a GPR109A agonist is an anthranilic acid GPR109A agonist (compound 22 of Boatman et al, 2008, J Med Chem 51 (24):7653- 7662) represented by Formula (XXXXVI):

|0327] In some embodiments of the present invention, a GPR109A agonist is an anthranil acid GPR109A agonist (compound 23 of Boatman et ai, 2008, J Med Chem 51 (24):7653- 7662) represented by Formula (XXXXVII):

[0328] In some embodiments of the present invention, a GPR109A agonist is an anthranil acid GPR109A agonist (compound 24 of Boatman et ai, 2008, J Med Chem 51 (24):7653- 7662) represented by Formula (XXXXVIII):

[0329] In some embodiments of the present invention, a GPR109 A agonist is an anthranilic acid GPR109A agonist (compound 25 of Boatman et al., 2008, J Med Chem 51 (24):7653- 7662) represented by Formula (XXXXIX):

[0330] In some embodiments of the present invention, a GPR109 A agonist is an anthranil acid GPR109A agonist (compound 32 of Boatman et al. , 2008, J Med Chem 51 (24):7653- 7662) represented by Formula (L):

[0331] In some embodiments of the present invention, a GPR109A agonist is an anthranilic acid GPR109A agonist (compound 33 of of Boatman et al., 2008, J Med Chem 51 (24): 7653- 7662) represented by Formula (LI):

[0332] In some embodiments of the present invention, a GPR109 A agonist is an anthranilic acid GPR109A agonist (compound 34 of of Boatman et ai , 2008, J Med Chem 51 (24):7653- 7662) represented by Formula LII):

[0333] In some embodiments of the present invention, a GPR109A agonist is a quinoxaline containing anthranilic acid GPR109A agonist (compound 26 of Boatman et ai, 2008, J Med Chem 51 (24):7653-7662) represented by Formula (LIII):

|0334] In some embodiments of the present invention, a GPR 109A agonist is a quinoxaline containing anthranilic acid GPR 109A agonist (compound 26 of Boatman et al. , 2008, J Med Chem 51 (24):7653-7662) represented by Formula (LIV):

[0335] Boatman et al. did not suggest to use a GPR109 A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0336] In some embodiments of the present invention, a GPR109A agonist is an anthranilic acid derivative GPR1 09A agonist as described by Deng et al , 2008, Bioorg Med Chem Lett 18( 1 8):4963-7; incorporated herewith by reference in its entirety).

[0337] In some embodiments of the present invention, a GPR109A agonist is an anthranilic acid derivative GPR109A agonist (compound l a of Deng et al.) represented by Formula (LV):

[0338] In some embodiments of the present invention, a GPR 1 09A agonist is an anthranil acid derivative GPR 1 09A agonist (compound l b of Deng et al. ) represented by Formula (LVI):

[0339] In some embodiments of the present invention, a GPR109A agonist is an anthranilic acid derivative GPR109A agonist (compound l c of Deng et al.) represented by Formula (LVII):

|0340] In some embodiments of the present invention, a GPR109 A agonist is an anthranil acid derivative GPR109A agonist (compound I d of Deng et al.) represented by Formula (LVIII):

[0341] In some embodiments of the present invention, a GPR109A agonist is an anthranil acid derivative GPR109A agonist (compound le of Deng et al.) represented by Formula (LIX):

[0342] Deng et al. did not suggest to use a GPR109 A agonist in a method to treat, prevent, or alleviate an ischemic condition.

12. Anthranilide GPR109A Agonists

[0343] In some embodiments of the present invention, a GPR 109A agonist is an anthranilide GPR109A agonist.

a) [6,6,5] Tricyclic Anthranilide GPR109A Agonists

[0344] In some embodiments of the present invention, a GPR109A agonist is a [6,6,5] tricyclic anthranilide GPR109A agonist.

[0345] In some embodiments of the present invention, a GPR109A agonist is a [6,6,5] tricyclic anthranilide GPR109A agonist as described by Shen et al. (2009, J Med Chem 52(8):2587-2602; incorporated herewith by reference in its entirety) and as shown in Figure 6 (compounds 2a through 2j) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0346] Shen et al. did not suggest to use a [6,6,5] tricyclic anthranilide GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0347] In some embodiments of the present invention, a GPR109 A agonist is selected from the group consisting of compound 2a, compound 2b, compound 2c, compound 2d, compound 2e, compound 2f, compound 2g, compound 2h, compound 2i, compound 2j as shown in Figure 6 and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

b) [6,5,5], [6,6,6], [5,6,6] Tricyclic And Naphthol Anthranilide GPR109A Agonists

[0348] In some embodiments of the present invention, a GPR109A agonist is a [6,5,5],

[6,6,6], [5,6,6] tricyclic and naphthol anthranilide GPR109A agonist. |0349] In some embodiments of the present invention, a GPR109 A agonist is a [6,5,5], [6,6,6], [5,6,6] tricyclic and naphthol anthranilide GPR109A agonist as described by Shen et al. (2009, J Med Chem 52(8):2587-2602; incorporated herewith by reference in its entirety) and as shown in Figure 7 (compounds 2k through 2q) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[03501 Shen et al. did not suggest to use a [6,5,5], [6,6,6], [5,6,6] tricyclic and naphthol anthranilide GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0351] In some embodiments of the present invention, a GPR109 A agonist is selected from the group consisting of compound 2k, compound 21, compound 2m, compound 2n, compound 2o, compound 2p, compound 2q as shown in Figure 7 and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

c) Biaryl Anthranilide GPR109A Agonists

[0352] In some embodiments of the present invention, a GPR109A agonist is a biaryl anthranilide GPR109A agonist.

[0353] In some embodiments of the present invention, a GPR109A agonist is a biaryl anthranilide GPR109A agonist as described by Shen et al. (2009, J Med Chem 52(8):2587- 2602; incorporated herewith by reference in its entirety) and as shown in Figure 8

(compounds l a through I d and compounds 2a through 2j) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0354] Shen et al. did not suggest to use a biaryl anthranilide GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0355] In some embodiments of the present invention, a GPR109A agonist is selected from the group consisting of compound la, compound l b, compound lc, compound Id, compound 2a, compound 2b, compound 2c, compound 2d compound 2e, compound 2f, compound 2g, compound 2h, compound 2i compound 2j as shown in Figure 8 and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

d) Biheteroaryl Anthranilide GPR109A Agonists

[0356] In some embodiments of the present invention, a GPR109A agonist is a biheteroaryl anthranilide GPR 109A agonist.

[0357] In some embodiments of the present invention, a GPR109A agonist is a biheteroaryl anthranilide GPR 109 A agonist as described by Shen et al. (2009, J Med Chem 52(8):2587- 2602; incorporated herewith by reference in its entirety) and as shown in Figure 9

(compounds 2k through 2o) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0358] Shen et al. did not suggest to use a biheteroaryl anthranilide GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0359] In some embodiments of the present invention, a GPR109A agonist is selected from the group consisting of compound 2k compound 21, compound 2m, compound 2n, compound 2o as shown in Figure 9 and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

13. Cycloalkene Carboxylic Acid GPR109A Agonists

[0360] In some embodiments of the present invention, a GPR109A agonist is cycloalkene carboxylic acid GPR109A agonist.

[0361] In some embodiments of the present invention, a GPR109A agonist is tricyclic cycloalkene carboxylic acid GPR109A agonist as described by Shen et al. (2009, J Med Chem 52(8):2587-2602; incorporated herewith by reference in its entirety) and as shown in Figure 10 (compounds 3a through 3h) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0362] Shen et al. did not suggest to use tricyclic cycloalkene carboxylic acid GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

[0363] In some embodiments of the present invention, a GPR109 A agonist is selected from the group consisting of compound 3a, compound 3b, compound 3c, compound 3d, compound 3e, compound 3f, compound 3g, compound 3h as shown in Figure 10, and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

14. GPR109A Agonists Comprising A Urea Moiety

[0364] In some embodiments of the present invention, a GPR109A agonist is a GPR109A agonist comprising a urea moiety.

[0365] In some embodiments of the present invention, a GPR109A agonist is a urea GPR109 A agonist as described by Shen et al. (2007, Bioorg Med Chem Lett 17(24):6723-8; incorporated herewith by reference in its entirety )and as shown in Figurel 1 (compounds l a through l x) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. [0366] In some embodiments of the present invention, a GPR109A agonist is selected from the group consisting of compound l a, compound l b, compound l c, compound I d, compound l e, compound I f, compound l g, compound l h, compound l i, compound lj, compound l k, compound 11, compound l m, compound I n, compound lo, compound l p, compound l q, compound lr, compound Is, compound It, compound lu, compound lv, compound lw, compound l as shown in Figure 1 1 , and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

[0367] In some embodiments, a urea GPR109A agonist is compound l a or a

pharmaceutically acceptable salt or solvate thereof (Figure 1 1). In other embodiments, a urea GPR109A agonist is compound 1 q or a pharmaceutically acceptable salt or solvate thereof (Figure 1 1).

[0368] Shen et al. did not suggest to use a urea GPR109 A agonist in a method to treat, prevent, or alleviate an ischemic condition.

15. 6-Membered Heterocyclic Acid GPR109A Agonists

[0369] In some embodiments of the present invention, a GPR109A agonist is a 6- membered heterocyclic acid GPR109A agonist.

[0370] In some embodiments of the present invention, a GPR109A agonist is a 6- membered heterocyclic acid GPR109A agonist as described by Gharbaoui et al. (2007, Bioorg Med Chem Lett 17(17):4914-9; incorporated herewith by reference in its entirety) and as shown in Figure 4A or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0371] In some embodiments of the present invention, a GPR109A agonist is selected from the group consisting of compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 1 1 , compound 12 as shown in Figure 4A, and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

[0372] Gharbaoui et al. did not suggest to use a urea a 6-membered heterocyclic acid GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

16. 5-Membered Heterocyclic Acid GPR109A Agonists

[0373] In some embodiments of the present invention, a GPR109A agonist is a 5- membered heterocyclic acid GPR109A agonist. [0374] In some embodiments of the present invention, a GPR109A agonist is a 5- membered heterocyclic acid GPR109A agonist as described by Gharbaoui et al. (2007, Bioorg Med Chem Lett 1 7( 17):4914-9; incorporated herewith by reference in its entirety)and as shown in Figure 4B or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

[0375] In some embodiments of the present invention, a GPR109 A agonist is selected from the group consisting of compound 13, compound 14, compound 15, compound 16, compound 17, compound 18, compound 19, compound 20, compound 21 as shown in Figure 4B, and pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

[0376] Gharbaoui et al. did not suggest to use a urea a 5-membered heterocyclic acid GPR109A agonist in a method to treat, prevent, or alleviate an ischemic condition.

17. Substituted Adenine GPR109A Agonists

[0377] In some embodiments of the present invention, a GPR109A agonist is a substituted adenine GPR 109 A agonist.

a) 9-Substituted Adenine GPR109A Agonists

[0378] In some embodiments of the present invention, a GPR109A agonist is a 9- subsitituted adenine GPR109A agonist.

[0379] In some embodiments of the present invention, a GPR109A agonist is a 9- subsitituted adenine GPR109A agonist as described by Credner et al. (\ 9S\ , Arzneim

Forsch/Drug Res 31 (1 1), No. 12 2096-2100; incorporated herewith by reference in its entirety) and as represented by Formula (LX):

wherein, R is alkyl, alkenyl, alkoxy, aryl, cycloalkyl or haloalkyl;

[0380] In some embodiments of the present invention, a GPR109A agonist is a 9- subsitituted adenine GPR 109A agonist as represented by Formula (LX), wherein R is methyl. [0381] In some embodiments of the present invention, a GPR109A agonist is a 9- subsitituted adenine GPR109A agonist as represented by Formula (LX), wherein R is ethyl.

[0382] In some embodiments of the present invention, a GPR109A agonist is a 9- subsitituted adenine GPR109A agonist as represented by Formula (LX), wherein R is propyl or isopropyl.

[0383] In some embodiments of the present invention, a GPR109A agonist is a 9- subsitituted adenine GPR109A agonist as represented by Formula (LX), wherein R comprises an ethanol group. b) 7-Substituted Adenine GPR109A Agonists

[0384] In some embodiments of the present invention, a GPR109 A agonist is a 7- subsitituted adenine GPR109A agonist.

[0385] In some embodiments of the present invention, a GPR109A agonist is a 7- subsitituted adenine GPR109A agonist as described by Credner et al. (1981 , Arzneim

Forsch/Drug Res 31(1 1), No. 12 2096-2100; incorporated herewith by reference in ks entirety) and as represented by Formula (LXI):

wherein, R is alkyl, alkenyl, alkoxy, aryl, cycloalkyl or haloalkyl;

[0386] In some embodiments of the present invention, a GPR109A agonist is a 7- subsitituted adenine GPR109A agonist as represented by Formula (LXI), wherein R is methyl.

[0387] In some embodiments of the present invention, a GPR109A agonist is a 7- subsitituted adenine GPR109A agonist as represented by Formula (LXI), wherein R is ethyl.

[0388] In some embodiments of the present invention, a GPR109A agonist is a 7- subsitituted adenine GPR109A agonist as represented by Formula (LXI), wherein R is propyl or isopropyl. [0389] In some embodiments of the present invention, a GPR109A agonist is a 7- subsitituted adenine GPR109A agonist as represented by Formula (LXI), wherein R comprises an ethanol group.

18. Additional GPR109A Agonists

[0390] In some embodiments of the present invention, a GPR109A agonist is a compound as shown in Figure 12.

[0391] In some embodiments, a GPR109A agonist is a GPR109A agonist as described in WO2006/057922 (Preparation of Biaryl Compounds, Particularly N-Biarylpropionyl) anthranilides, as Niacin Receptor Agonists and Pyridoindolizine Derivatives as DP Receptor Antagonists, Their Pharmaceutical Compositions and Their Combination Useful for Treating Atherosclerosis and Dyslipidemias), WO2006/1 13 150 (Preparation of Pyrazole Derivatives as Niacin Receptor Agonists), WO2005/01 1677 (Preparation of 5-Substituted 2H-Pyrazole-3- carboxylic Acid Derivatives as Agonists for the RUP25 Nicotinic Acid Receptor for the Treatment of Dyslipidemia and Related Diseases), WO2005/044816 (Preparation of

Tetrazole Derivatives, Useful as Modulators of RUP25 Receptor), WO2006/069242 (Fused Pyrazole Derivatives and Methods of Treatment of Metabolic-Related Disorders Thereof), WO2006/052555 (N-Acyl Anthranilic Acid and Related Compounds as Niacin Receptor Agonists, and Their Preparation, Pharmaceutical Compositions and Methods of Treatment of Dyslipidemias), WO2006/0851 13 (Preparation of Heteroaryl Carboxylic Acid Derivatives for Treatment of Diseases Characterized by Under Activation of HM74A Receptor),

WO2006/0851 1 1 (Preparation of Anthranilic Acid Derivatives Treating Diseases Active at the hm74a Receptor), WO2006/0851 12 (Preparation of Anthranilic Acid Derivatives Treating Diseases Active at the HM74A Receptor), WO2005/016870 (Preparation of Anthranilic Acid Derivatives as Selective Agonists of the Nicotinic Acid Receptor HM74A), WO2005/016867 (Preparation of Anthranilic Acid Derivatives as Selective Agonists of the Nicotinic Acid Receptor HM74A), WO2007/015744 (Preparation of Disubstituted Thienyl Compounds as HM74a Receptor Modulators), WO2007/092364 (Preparation of

Carboxamidocyclohexenylcarboxylic Acids Derivatives as Niacin Receptor Agonists, Compositions Containing Such Compounds and Methods of Treatment), WO2008/051403 (Niacin Receptor Agonists, Compositions Containing Such Compounds and Methods of Treatment), WO2006/045565 (Preparation of Halogenoalkyl Xanthine Derivatives as HM74A Agonists), WO2006/045564 (Preparation of Xanthine Derivatives as HM74A Agonists), WO2005/077950 (Preparation of Xanthine Derivatives as HM74A Agonists), WO2007/150025 (Preparation of Purinone Derivatives as HM74a Agonists), WO2007/150026 (Purinone Derivatives as HM74a Receptor Agonists and Their Preparation, Pharmaceutical Compositions and Use in the Treatment of Diseases), U.S. Pat. Appl. Publ. No. 2005/187263 (Methods for Identifying Oxydecahydronaphthalene Modulators of hm74and Therapeutic Uses for Inflammation), U.S. Pat. Appl. Publ. No. 2005/1 87280 (Furosemide Modulators of HM74), U.S. Pat. Appl. Publ. No. 2008/019978 (Pyrano[2,3- cTJpyrimidines as Nicotinic Acid Receptor Agonists for the Treatment of Dyslipidemia and Their Preparation and Pharmaceutical Compositions), each of which is incorporated herewith by reference in its entirety.

19. Modifications of GPR109A Agonists

[0392] In some embodiments, a GPR109A agonist is chemically modified or one or more group is substituted by another chemical group. Such modifications may improve a relatively low potency and/or an unfavorable pharmacokinetic property of a GPR109A agonist. In some embodiments, a GPR109A agonist carries at least a carboxylate group. Thus, in some embodiments, the common feature of GPR109A agonists is the presence of a carboxylic group. It has been found that changes or substitutions at the carboxylic acid moiety of nicotinic acid, such as nicotinamide, completely abrogates its pharmacological activity (Tunaru et al. , 2005, Mol Pharmacol 68: 1271 - 1280).

[0393] Partial agonism of a candidate GPR109A agonist can be tested by inhibition of G protein activation in response to nicotinic acid by these compounds. A partial GPR109A agonist inhibits the maximum effect elicited by 100 μΜ nicotinic acid and concentration dependently shifts nicotinic acid concentration-response curves to the right, pointing to a competitive mechanism of action.

[0394] A strategy for identification of new agonists for GPR109A, starting from known compounds shown to activate GPR109A has been described by Gharbaoui et al. (2007, Bioorg Med Chem Lett 17(17):4914-9). The strategy described therein can be employed by one of skill in the art to identify additional GPR109A agonists that are useful to practice methods of the present invention.

20. Steric Isomers

[0395] The GPR 109A agonists for use in the invention may exist in (+) and (-) forms as well as in racemic forms. The use of racemates of these isomers and the individual isomers themselves are within the scope of the present invention. 21. Pharmaceutically Acceptable Salts

[0396] The GPR109A agonists for use in the invention may be provided in any form suitable for the intended administration. In some embodiments of the present invention, a GPR109A agonist is provided as a pharmaceutically (i.e. physiologically) acceptable salt of a GPR109A agonist for use according to the invention. In other embodiments of the present invention, a GPR109 agonist is provides as a pharmaceutically (i.e. physiologically) acceptable solvate of a GPR109A agonist for use according to the invention.

[0397] In some embodiments of the present invention, a pharmaceutically acceptable addition salt includes, without limitation, a non-toxic inorganic and organic acid addition salt such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, the glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate derived, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulphonate, and the like. Such salts may be formed by procedures well known and described in the art.

[0398] In some embodiments of the present invention, a GPR109A agonist for use according to the invention is used in form of a metal salt, e.g., including, but not limited to, an alkali metal salt such as the sodium salt of a GPR109A agonist containing a carboxy group.

[0399] In other embodiments, the pharmaceutically acceptable salt of a GPR109A agonist is an alkaline or alkaline earth salt or a salt with a mineral or organic acid, in anhydrous or hydrated form.

22. Prodrugs

[0400] The GPR109A agonists for use in the invention may be provided in any form suitable for the intended administration. In some embodiments of the present invention, a GPR109A agonist is provided as a pre- or prodrug form of a GPR109A agonist for use according to the invention.

[0401] In some, embodiments, prodrugs of this invention include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, (3-lactam-containing prodrugs, optionally substituted phenoxyacetamide- containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, 5 fluorocytosine and other 5-fluorouridine prodrugs which can be converted into the more active cytotoxic free drug. Examples of cytotoxic drugs that can be derivatized into a prodrug form for use in this invention include, but are not limited to, those chemotherapeutic agents described above.

[0402] Examples of suitable prodrugs of a GPR109A agonist according to the invention includes a GPR109A agonist modified at one or more reactive or derivatizable groups of the parent compound. Of particular interest are GPR109A agonists modified at a carboxyl group, a hydroxyl group, or an amino group. Examples of suitable derivatives are esters or amides.

B. Binding Of GPR109A Agonists To GPR109A And Activation Of

GPR109A

[0403] Binding of an agonist to GPR109A can be determined by various methods. In some embodiments of the present invention, a GPR109A agonist is radiolabeled, i.e., a radioligand is made. Characterization and binding of a GPR109A agonist radioligand to a GPR109A can be determined as described in the art, e.g., in Tunaru et al. (2005, Mol Pharmacol 68: 1271 - 1280).

[0404] Specificity of an agonist binding to GPR109A can be assessed by comparing the binding of a labeled GPR109A agonist to a wild-type GPR109A receptor to the binding of the same labeled GPR109A agonist to a mutant GPR109A (Tunaru et al, 2005, Mol Pharmacol 68: 1271-1280) or to a GPR109B (HM74) receptor having a high degree of sequence homology to GPR109A (Soga et al, 2003, Biochem Biophys Res Commun

303:364-369; Wise et al, 2003, J Biol Chem 278:9869-9874). An agonist binding stronger or at a lower concentration to GPR109A than to a GPR109A mutant or GPR109B shows specific binding to GPR109A.

[0405] GPR109A agonist induced activation of (i) GPR109A, (ii) a mutant GPR109A, or (iii) GPR109B can also be tested in cells expressing such receptors and the promiscuous G- protein a-subunit Got] 5 or other promiscuous G-proteins in a Ca²⁺ reporter assay as described previously (Tunaru et al, 2003, Nat Med 9:352-355).

[0406] Activation of GPR109A by a GPR109A agonist or candidate GPR109A agonist can be measured, e.g., by determining adenylyl cyclase inhibition or using a MAP kinase assay (Richman et al, 2007, J Biol Chem 282(25): 18028-36; see also Examples herein).

[0407] GPR109A agonists described herein can also be tested for their efficacy, toxicity, etc. in a rat or dog model system as described by Carballo-Jane et al (2007 J Pharmacol Toxicol Methods 56(3):308-16), by determination of increased blood flow in a mouse ear by laser doppler measurement (Benyo et al , 2005, J Clin Invest 1 1 5: 3634-3640), and in a mouse model described herein (see Examples).

III. PHARMACEUTICAL COMPOSITIONS

[0408] In one aspect the present invention provides pharmaceutical compositions or medicaments comprising at least one compound of the present invention and optionally a pharmaceutically acceptable carrier. A pharmaceutical composition or medicament can be administered to a patient for the treatment, prevention or alleviation of an ischemic condition described herein. A. Formulations and Administrations

[0409] The compounds of the present invention, GPR109A agonists, are useful in the manufacture of a pharmaceutical composition or a medicament comprising an effective amount thereof in conjunction or mixture with excipients or carriers suitable for either enteral or parenteral application.

[0410] Pharmaceutical compositions or medicaments for use in the present invention can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in "Remington's Pharmaceutical Sciences" by E.W. Martin. The compounds of the present invention and their physiologically acceptable salts and solvates can be formulated for administration by any suitable route, including via inhalation, topically, nasally, orally, parenterally, or rectally. Thus, the administration of the pharmaceutical composition may be made by intradermal, subdermal, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary or intratumoral injection, with a syringe or other devices. Transdermal administration is also contemplated, as are inhalation or aerosol administration. Tablets and capsules can be administered orally, rectally or vaginally.

[0411] For oral administration, a pharmaceutical composition or a medicament can take the form of, for example, a tablet or a capsule prepared by conventional means with a pharmaceutically acceptable excipient. Preferred are tablets and gelatin capsules comprising the active ingredient, i.e., a composition of the present invention, together with (a) diluents or fillers, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylates and/or calcium hydrogen phosphate, calcium sulfate, (b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, metallic stearates, colloidal silicon dioxide, hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate and/or polyethyleneglycol; for tablets also (c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and/or hydroxypropyl methylcellulose; if desired (d) disintegrants, e.g., starches (e.g., potato starch or sodium starch), glycolate, agar, alginic acid or its sodium salt, or effervescent mixtures; (e) wetting agents, e.g., sodium lauryl sulphate, and/or (0 absorbents, colorants, flavors and sweeteners.

[0412) Tablets may be either film coated or enteric coated according to methods known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, for example, suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats;

emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for example, methyl or propyl-p-hydroxybenzoates or sorbic acid. The preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated to give controlled release of the active composition.

[0413] For administration by inhalation the compounds may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 , 1 ,2-tetrafluorethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, for example, lactose or starch.

[0414] The compounds of the present invention can be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion.

Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient, i.e., an GPR109A agonist.

[0415) Suitable formulations for transdermal application include an effective amount of a composition of the present invention with carrier. Preferred carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the composition optionally with carriers, optionally a rate controlling barrier to deliver the composition to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations may also be used.

[0416] Furthermore, the compositions can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the composition can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0417] In some embodiments of the present invention, a pharmaceutical composition or medicament comprises an effective amount of a compound of the present invention, i.e., a GPR109A agonist, and another therapeutic agent. Such pharmaceutical compositions are useful for a combination therapy.

B. Dosing

[0418] In one embodiment of the present invention, a pharmaceutical composition or medicament is administered to a patient at a therapeutically effective dose to treat, prevent, or alleviate an ischemic condition. The pharmaceutical composition or medicament is administered to a patient in an amount sufficient to elicit an effective therapeutic response in the patient. An effective therapeutic response is a response that at least partially arrests or slows the symptoms or complications of ischemic condition. An amount adequate to accomplish this is defined as "therapeutically effective dose." [0419] The dosage of active compounds or compositions administered is dependent on the species of warm-blooded animal (mammal), the body weight, age, individual condition, surface area of the area to be treated and on the form of administration. The size of the dose also will be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular compound in a particular subject.

[0420] Generally, a GPR109A agonist will be administered in an amount ranging from as low as about 0.01 mg/day to as high as about 2000 mg/day, in single or divided doses. An exemplary dosage range is about 0.1 mg/day to about 1 g/day. Lower dosages can be used initially. Dosages can be increased to further minimize any untoward effects. It is expected that the GPR109A agonists described herein will be administered on a daily basis for a length of time appropriate to treat, prevent, or alleviate the medical condition relevant to the patient, including a course of therapy lasting months, years or the life of the patient. Examples of suitable dosage amounts include approximately 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 60 mg, 75 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900mg 1 ,000 mg, 1 ,200 mg,

1 ,500 mg, 1 750 mg, 2,000 mg and the like. An exemplary unit dosage for administration to a mammal of about 50 to 70 kg may contain between about 5 and 500 mg of the active ingredient, i.e., a GPR109 A agonist. Typically, a dosage of the compound of the present invention, is a dosage that is sufficient to achieve the desired effect.

[0421] Optimal dosing schedules can be calculated from measurements of compound accumulation in the body of a subject. In general, dosage is from 1 ng to 1 ,000 mg per kg of body weight and may be given once or more daily, weekly, monthly, or yearly. Persons of ordinary skill in the art can easily determine optimum dosages, dosing methodologies and repetition rates. One of skill in the art will be able to determine optimal dosing for administration of a GPR109A agonist to a subject following established protocols known in the art and the disclosure herein.

[0422] Optimum dosages, toxicity, and therapeutic efficacy of some compounds may vary depending on the relative potency of individual compounds and can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio, LD50/ED50. Compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue to minimize potential damage to normal cells and, thereby, reduce side effects.

[0423] The data obtained from, for example, animal studies (e.g. rodents, dogs and monkeys; Carballo-Jane et al. 2007 , J Pharmacol Toxicol Methods 56(3):308-16) can be used to formulate a dosage range for use in humans. The dosage of compounds of the present invention lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration. For any small molecule compound used in the methods of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography (HPLC). In general, the dose equivalent of a small molecule compound is from about 1 ng/kg to 100 mg/kg for a typical subject.

[0424] The dosage of active compositions administered is also dependent on the nature of the GPR109A agonist. In some embodiments, a therapeutically effective amount of a GPR109A agonist of the present invention (i.e., an effective dosage) for, e.g., treatment of an ischemic condition, ranges from about 0.001 to 30 mg/kg body weight, preferably from about 0.01 to 25 mg/kg body weight, more preferably from about 0.1 to 20 mg/kg body weight, and even more preferably from about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.

[0425] Exemplary doses of the compositions described herein, include milligram or microgram amounts of the composition per kilogram of subject or sample weight (e.g., about 1 microgram per-kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram. It is furthermore understood that appropriate doses of a composition depend upon the potency of the composition with respect to the desired effect to be achieved. When one or more of these compositions is to be administered to a subject, a physician or researcher may, for example, prescribe a relatively low dose at first,

subsequently increasing the dose until an appropriate response is obtained. In addition, it is understood that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific composition employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.

[0426] In some embodiments of the present invention, a pharmaceutical composition or medicament comprising a GPR109A agonist of the present invention is administered, e.g., in a daily dose in the range from about 1 mg of compound per kg of subject weight (1 mg/kg) to about lg/kg. In other embodiments, the dose is a dose in the range of about 5 mg/kg to about 500 mg/kg. In yet other embodiments, the dose is about 10 mg/kg to about 250 mg/kg. In some embodiments, the dose is about 25 mg/kg to about 150 mg/kg. In some embodiments, the dose is about 10 mg/kg. The daily dose can be administered once per day or divided into subdoses and administered in multiple doses, e.g., twice, three times, or four times per day. However, as will be appreciated by a skilled artisan, compositions of the present invention may be administered in different amounts and at different times. The skilled artisan will also appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the ischemic condition, previous treatments, the general health and/or age of the subject, and other diseases present.

Moreover, treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or, preferably, can include a series of treatments.

[0427] To achieve the desired therapeutic effect, compositions may be administered for multiple days at the therapeutically effective daily dose. Thus, therapeutically effective administration of compositions to treat an ischemic condition described herein in a subject requires periodic (e.g., daily) administration that continues for a period ranging from three days to two weeks or longer. Typically, compounds or compositions will be administered for at least three consecutive days, often for at least five consecutive days, more often for at least ten, and sometimes for 20, 30, 40 or more consecutive days. While consecutive daily doses are a preferred route to achieve a therapeutically effective dose, a therapeutically beneficial effect can be achieved even if the compounds or compositions are not administered daily, so long as the administration is repeated frequently enough to maintain a therapeutically effective concentration of the compound in the subject. For example, one can administer a compound or composition every other day, every third day, or, if higher dose ranges are employed and tolerated by the subject, once a week.

[0428] Following successful treatment of an ischemic condition, it may be desirable to have the subject undergo maintenance therapy to prevent the recurrence of the ischemic condition treated. IV. METHODS

A. Treatment Of An Ischemic Condition

[0429] Compositions of the present invention can be used in methods for the prevention and treatment of various disease and conditions.

[0430] In some embodiments, the disease to be treated, prevented or alleviated is selected from an ischemic condition, an anoxic episode, and injury to the brain and other parts of the CNS caused by trauma or other injury, for example a blow to the head. In such reduced blood flow episodes, or episodes where there is a temporary break in blood supply, oxygen supply to the brain is reduced or interrupted.

[0431] In other embodiments, the disease to be treated, prevented or alleviated is selected from cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as tromboembolic or haemorrhagic stroke, cerebral vasospasm, hypoglycaemia, cardiac arrest, perinatal asphyxia, anoxia such as from near-drowning, pulmonary surgery and cerebral trauma.

[0432] In other embodiments, the disease to be treated, prevented or alleviated is an ischemic condition. An ischemic condition (also referred to herein from time to time as an ischemic event) which can be treated, prevented or alleviated by a method of the present invention may result from coronary artery bypass graft surgery, cerebral ischemia, focal cerebral infarction, cerebral hemorrhage, hemorrhage infarction, hypertensive hemorrhage, intracranial vascular hemorrhage, subarachnoid hemorrhage, hypertensive encephalopathy, carotid stenosis or occlusion, cardiogenic thromboembolism, spinal stroke, spinal cord injury, atherosclerosis, vasculitis, macular degeneration, myocardial infarction, cardiac ischemia and supraventricular tachyarrhythmia. In some embodiments, an ischemic condition is a cerebral ischemia.

[0433] The present invention provides methods for the treatment, prevention or alleviation of traumatic brain injury, in particular ischemic, hypoxic or anoxic brain damage, spinal cord injury, tissue ischemia and reperfusion injury in a mammal at risk for such damage. The brain damage may follow or be caused by cerebral ischemia, cardiac arrest, high-risk surgery such as cardiac surgery, stroke, neonatal hypoxia, hypoxia caused by compromised lung function, neonatal anoxia, anoxia caused by compromised lung function, cerebral trauma, secondary regional ischemia induced by brain oedema, increased intercranial pressure, open brain surgery, endarterectomy, surgical interventions involving temporary, artificially sustained arrest of cardiopulmonary functions resulting in impairment of cerebral blood flow, and emergency treatment involving cardiopulmonary resuscitation (CPR).

[0434] In other embodiments the invention provides methods for the treatment, prevention or alleviation of ischemic stroke, treatment of brain damage following global cerebral ischemia, or prevention of brain damage following high risk surgery.

[0435] In some embodiments of the present invention, a method for the treatment of an ischemic condition in a patient in need thereof, comprises administering to said patient a pharmaceutical composition comprising an agonist of a GPR109A receptor in an amount effective to treat the ischemic condition. In other embodiments, a therapeutically effective amount of a GPR 109 A agonist is administered to said patient.

[0436] In some embodiments of the present invention, a method for the prevention of an ischemic condition in a patient in need thereof, comprises administering to said patient a pharmaceutical composition comprising an agonist of a GPR 109 A receptor in an amount effective to prevent the ischemic condition. In other embodiments, a therapeutically effective amount of a GPR109A agonist is administered to said patient.

[0437] In some embodiments of the present invention, a method for the alleviation of an ischemic condition in a patient in need thereof, comprises administering to said patient a pharmaceutical composition comprising an agonist of a GPR 109 A receptor in an amount effective to alleviate the ischemic condition. In other embodiments, a therapeutically effective amount of a GPR109A agonist is administered to said patient.

[0438] In some embodiments, the methods comprise the step of selecting a subject being afflicted with an ischemic condition.

[0439] In some embodiments of the present invention, the method for the treatment of cerebral ischemia in a subject, comprises administering to said subject a therapeutically effective amount of a GPR109 A agonist or a pharmaceutically acceptable salt or solvate thereof to treat the cerebral ischemia.

[0440] In some embodiments of the present invention, the method for the prevention of cerebral ischemia in a subject, comprises administering to said subject a therapeutically effective amount of a GPR 109 A agonist or a pharmaceutically acceptable salt or solvate thereof to prevent the cerebral ischemia.

[0441] In some embodiments of the present invention, the method for the alleviation of cerebral ischemia in a subject, comprises administering to said subject a therapeutically effective amount of a GPR109A agonist or a pharmaceutically acceptable salt or solvate thereof to alleviate the cerebral ischemia.

[0442] In some embodiments, the methods comprise the step of selecting a subject being afflicted with cerebral ischemia.

[0443] The present invention also provides methods of treating a subject with stroke or who is of high risk for a stroke because of having experienced a previous ischemic event, to reduce the occurrence of neuronal damage and associated neurological dysfunction in a stroke compared to that which normally occurs. In some embodiments, this method comprises the step of administering to said subject a pharmaceutical composition comprising an agonist of a GPR109A receptor in an amount effective to treat the subject with stroke or who is of high risk for a stroke. In other embodiments, a therapeutically effective amount of a GPR109A agonist is administered to s the subject with stroke or who is of high risk for a stroke. .

[0444] In some embodiments, the methods comprise the step of selecting or identifying a subject having a high risk for a stroke. In some embodiments, a subject having a high risk for a stroke is a subject having experienced a previous ischemic event. In other embodiments, a subject having a high risk for a stroke, is a subject having one or more of the following risk factors: arterial hypertension, hypercholesterolemia, diabetes, smoking, auricular fibrillation, an embolic heart disease, or increasing age.

[0445] The present invention further provides a method of treatment of a subject currently afflicted with a stroke or previously afflicted with an ischemic event. In some embodiments, this method comprises the step of administering to said subject a therapeutically effective amount of a GPR109A agonist.

[0446] In some embodiments, the methods comprise the step of selecting or identifying a subject currently afflicted with a stroke or previously afflicted with an ischemic event.

[0447J When selecting or identifying a subject being afflicted with a an ischemic condition, such as cerebral ischemia, one of skill in the art will look for one or more of the following symptoms in a candidate subject: (i) headache, (ii) muscle weakness in the face, arm, or leg (usually just one side), (iii) numbness tingling on one side of the body, (iv) trouble speaking or understanding others, (v) problems with eyesight, (e.g., decreased vision, double vision, or total loss of vision), (vi) sensation changes that affect touch and the ability to feel pain, pressure, different temperatures, or other stimuli, (vii) changes in hearing, (viii) changes in alertness (including sleepiness, unconsciousness, and coma), (ix) personality, mood or emotional changes, (x) confusion or loss of memory, (xi) difficulty swallowing, (xii) changes in taste, (xiii) difficulty in writing or reading, (xiv) loss of coordination, (xv) loss of balance, (xvi) clumsiness, (xvii) trouble walking, (xviii) trouble walking, (xix) dizziness or abnormal sensation of movement (vertigo), or (xx) lack of control over the bladder or bowels.

[0448] A headache is pain or discomfort in the head, scalp, or neck. The headache typically starts suddenly and may be severe. It may occur when the subject is lying flat. It may occur when the subject wakes up from sleep. The headache may get worse when the subject changes position, bends, strains, or coughs.

[0449] The symptoms of stroke depend on what part of the brain is damaged. In some cases, a subject may not even be aware that he or she has had a stroke. Symptoms usually develop suddenly and without warning, or they may occur on and off for the first day or two. Symptoms are usually most severe when the stroke first happens, but they may slowly get worse

[0450] In some embodiments of the methods, an effective amount of a GPR109A agonist or a pharmaceutically acceptable salt or solvate thereof is administered in daily doses in equivalent amounts of free GPR109 A agonist ranging from l g to 2g. This is the

concentration range used for nicotinic acid in order to obtain changes in plasma lipid levels. Other GPR109A agonists described herein may have different potencies and efficacies resulting in lower or higher doses required for pharmacological effects. Potencies and efficacies of GPR109A agonists may be determined using assays described herein.

B. Prophylactic Treatment Of An Ischemia Condition

[0451] The present invention also provides methods for the prophylactic treatment of an ischemia condition, such as cerebral ischemia. In some embodiments, the method for the prophylactic treatment of cerebral ischemia comprises administering to a subject in need thereof an effective amount of a GPR109 A agonist or a pharmaceutically acceptable salt or solvate thereof prior to an onset of a first cerebral ischemic event in said subject.

[0452] Thus, in some embodiments the step of administering an effective amount of a GPR109A agonist or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof is performed prior to the onset of a first ischemic event. [0453] In some embodiments, the method comprises the step of selecting or identifying a subject not having experienced a first ischemic event but being in need of administering an effective amount of a GPR109A agonist or a pharmaceutically acceptable salt or solvate.

C. Decreasing Severity Of An Infarct

[0454] Cerebral ischemia often leads to the formation of an infarct and neurological impairment. Compositions of the present invention can be used in methods for the decreasing infarct, sometimes referred to as infarct size or severity of infarct.

[0455] The present invention also provides methods for decreasing the severity of an infarct in a subject afflicted with a cerebral ischemia having caused said infarct size. In some embodiments of the present invention, this method comprises the step of administering to said subject a therapeutically effective amount of a GPR109A agonist or a pharmaceutically acceptable salt or solvate thereof to decrease the infarct size.

[0456] In some embodiments, the method comprises the step of diagnosing a stroke. In some embodiments diagnosing a stroke is performed by a clinical examination of a neurological deficit. In other embodiment, diagnosing a stroke is performed by a CT scan of the brain or the spinal cord. In yet other embodiments, diagnosing a stroke is performed by an MR scan of the brain or the spinal cord. This is typically done prior to the administration of the GPR109A agonist. Diagnosing a stroke and administering the GPR109A agonist may be done by the same practitioner or by different practitioners, at different locations and at different times. For example, the severity of an infarct is determined by a first practitioner shortly after a subject has been diagnosed having an ischemic condition, such as cerebral ischemia. In some embodiments of the present invention, the location and/of approximate infarct size (severity of infarct) is determined using CT or MR imaging. This information is conveyed to a second practitioner. The second practitioner obtaining or receiving this information then administers a GPR109A agonist. Determining the severity of an infarct and a neurological deficit (e.g., paresis, aphasia, sensory loss, visual disturbance, or vertigo) after administration of the GPR109A agonist may be done at various times and at multiple times after the administration of the GPR109A agonist to determine the efficacy of the GPR109A agonist in decreasing the severity of an infarct.

[0457] A decrease in infarct size or a decrease in the severity of an infarct or neurological deficit may be measured at any time after administering a GPR109A agonist, e.g., after 12 hours, after 1 day, after 2 days, after 3 days, after 1 week. [0458] The present invention also provides methods for preventing an increase of an infarct size or preventing an increase in the severity of an infarct in a subject afflicted with a cerebral ischemia having caused said infarct size or severity of infarct. In some embodiments of the present invention, this method comprises the step of administering to said subject a therapeutically effective amount of a GPR109A agonist or a pharmaceutically acceptable salt or solvate thereof to prevent an increase of the infarct size.

[0459] In some embodiments, the methods comprise the step of selecting a subject being afflicted with an infarct. Based on the clinical history of a sudden neurological deficit(e.g., paresis, aphasia, sensory loss, visual disturbance, or vertigo) and a clinical evaluation showing some degree of impairment, a stroke patient may be evaluated by imaging of the brain or the spinal cord. Infarcts can be delineated by a CT or MR scan of the head or spine.

[0460] The present invention also provides methods for alleviating in a subject one or more symptoms caused by an ischemic condition, such as cerebral ischemia. In some

embodiments of the present invention, this method comprises the step of administering to said subject a therapeutically effective amount of a GPR 109 A agonist or a pharmaceutically acceptable salt or solvate thereof to alleviate said one or more symptoms.

[0461] In some embodiments, the methods comprise the step of selecting a subject having one or more symptoms caused by an ischemic condition, such as cerebral ischemia.

D. Combined Treatment

[0462] The pharmaceutical composition for use according to the invention may include or may be used or administered in combination with one or more additional drug(s) useful for the treatment, prevention or alleviation of a disease associated with reduced blood flow to the brain or with an instance of a temporary break in blood supply to the brain. Such additional drugs include compounds known in the art and described herein, e.g., thrombolytic drugs, inhibitors of platelet aggregation such as aspirin or clopidogrel, statins, ACE inhibitors, antiinflammatory agents, compounds capable of blocking excitatory amino acid receptors (glutamate and aspartate) and compounds having neurotrophic activity.

[0463] Compounds having neurotrophic activity include, but are not limited to NGF, BDNF, ADNF, and/or GDNF. Compounds that enhance the function of NGF, BDNF, ADNF, and/or GDNF can also be combined with a GPR1 09A agonist of the invention or can be co-administered with a GPR109A agonist in methods of the present invention.. [0464] In some embodiments, the additional drug co-administered with a GPR109A agonist is a lipid modifying compound or an active agent having other pharmaceutical activities. Examples of additional active agents which may be coadministered with a GPR109A agonist include, but are not limited to HMG-CoA reductase inhibitors, which include statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin (see US Patent No. 4,342,767), simvastatin (see US Patent No. 4,444,784), dihydroxy open-acid simvastatin, particularly the ammonium or calcium salts thereof, pravastatin, particularly the sodium salt or solvate thereof (see US Patent No. 4,346,227), fluvastatin particularly the sodium salt or solvate thereof (see US Patent No. 5,354,772), atorvastatin, particularly the calcium salt or solvate thereof (see US Patent No. 5,273,995), pitavastatin also referred to as NK- 104 (see PCT international publication number WO 97/23200) and rosuvastatin, also known as CRESTOR^®; see US Patent No. 5,260,440); HMG-CoA synthase inhibitors; squalene epoxidase inhibitors;

squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acy transferase (ACAT) inhibitors including selective inhibitors of ACAT-I or ACAT-2 as well as dual inhibitors of ACAT-I and -2; microsomal triglyceride transfer protein (MTP) inhibitors; endothelial lipase inhibitors; bile acid sequestrants; LDL receptor inducers; platelet aggregation inhibitors, for example glycoprotein Ilb/IIla fibrinogen receptor antagonists and aspirin; human peroxisome proliferator activated receptor gamma (PPAR- gamma) agonists including the compounds commonly referred to as glitazones for example pioglitazone and rosiglitazone and, including those compounds included within the structural class known as thiazolidine diones as well as those PPAR-gamma agonists outside the thiazolidine dione structural class; PPAR-alpha agonists such as clofibrate, fenofibrate including micronized fenofibrate, and gemfibrozil; PPAR dual alpha/gamma agonists;

vitamin Ββ (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HC1 salt; vitamin B12 (also known as cyanocobalamin); folic acid or a

pharmaceutically acceptable salt or ester thereof such as the sodium salt and the

methylglucamine salt; anti-oxidant vitamins such as vitamin C and E and beta carotene; beta- blockers; angiotensin II antagonists such as losartan; angiotensin converting enzyme inhibitors such as enalapril and captopril; renin inhibitors, calcium channel blockers such as nifedipine and diltiazem; endothelin antagonists; agents that enhance ABCAI gene expression; cholesteryl ester transfer protein (CETP) inhibiting compounds, 5-lipoxygenase activating protein (FLAP) inhibiting compounds, 5-lipoxygenase (5-LO) inhibiting compounds, farnesoid X receptor (FXR) ligands including both antagonists and agonists; Liver X Receptor (LXR)-alpha ligands, LXR- beta ligands, bisphosphonate compounds such as alendronate sodium; cyclooxygenase-2 inhibitors such as rofecoxib and celecoxib; and compounds that attenuate vascular inflammation. Cholesterol absorption inhibitors can also be used in the present invention. Such compounds block the movement of cholesterol from the intestinal lumen into enterocytes of the small intestinal wall, thus reducing serum cholesterol levels. Examples of cholesterol absorption inhibitors are described in U.S. Patent Nos. 5,846,966, 5,631 ,365, 5,767, 1 1 5, 6, 133,001 , 5,886, 171 , 5,856,473, 5,756,470,

5,739,321 , 5,919,672, and in PCT application Nos. WO 00/63703, WO 00/60107, WO 00/38725, WO 00/34240, WO 00/20623, WO 97/45406, WO 97/16424, WO 97/16455, and WO 95/08532. The most notable cholesterol absorption inhibitor is ezetimibe, also known as l-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]- 4(S)-(4-hydroxyphenyl)- 2-azetidinone, described in U.S. Patent Nos. 5,767, 1 15 and 5,846,966). In some

embodiments, the additional drug co-administered with a GPR109A agonist is statin. In some embodiments, the additional drug co-administered with a GPR109A agonist is a PPAR- γ inhibitor.

E. General Treatment Considerations

[0465] In some embodiments of the treatment methods described herein, the subject is a human.

[0466] The route of administration can be any method by which the GPRl 09 A agonist crosses the blood-brain barrier in sufficient amount to protect neuronal cells from death. Crossing the blood-brain barrier is typically not a problem for GPRl 09 A agonist. In addition, the blood-brain barrier is usually disrupted in cerebral ischemia.

1. Subject Afflicted With Ischemic Condition

[0467] In many instances of cerebral ischemia, treatment is not available to a patient for several hours, e.g., up to 6 hours, in stroke patients typically 3 to 6 hours, after the ischemic injury. Such a delay places great demands on any therapeutic regime designed to mitigate ischemic brain injury. As described herein, GPR109A agonists of the present invention may be administered pre-ischemically or post-ischemically. When administered post-ischemically it is advisable that the GPR109A agonists be administered within one day of the ischemic insult. Preferably, the treatment with a GPR109A agonist of the present invention should be carried out within 12 hours of ischemic alleviation or reperfusion. Preferably, the treatment should occur within 6 hours of alleviation of ischemia. Yet more preferred is the

administration of a GPRl 09 A agonist within 3 hours of alleviation of ischemia. For a subject afflicted with a stroke, therapy pursuant to the invention very preferably should occur as soon as diagnosis occurs. In order to obtain a rapid response while minimizing risk, the administration of a GPR109A agonist should be via a parenteral route and in a neuronal cell protecting amount, i.e., an amount which reduces neuronal cell death compared to that which would occur if the stroke were untreated.

[0468] The therapeutically effective amount for a subject with a stroke is a neuronal cell protecting amount, i.e., an amount which reduces neuronal cell death compared to that which would occur if the stroke were untreated. Cells known to be killed during a stroke include hippocampal neurons, cortical neurons, caudate and putaminol neurons, cerebellar neurons and brain stem neurons. Since, of these, hippocampal neurons are known to be the most sensitive to strokes, the therapeutically effective amount is preferably a hippocampal neuron protecting amount, i.e., an amount which reduces hippocampal neuron death compared to that which would occur if the stroke were untreated. In general a therapeutically effective amount for those with a stroke is a non-toxic amount in the range of 0.05 mg/kg to 1000 mg/kg. The dose preferably ranges from 1 mg kg to 500 mg/kg, more preferably from 5 mg/kg to 250 mg/kg and even more preferrably from 50 mg/kg to 100 mg/kg.

[0469] For a subject afflicted with a stroke in progress, parenteral administration of a GPR109A agonist is preferred in order to obtain a fast response, very preferably intravenous administration, intraarterial administration or intraventricular administration via a cerebral spinal fluid route.

2. Subject At Risk For An Ischemic Condition

[0470] A subject who has experienced a previous ischemic event, e.g., a previous transient ischemic attack, a previous residual ischemic neurological deficit or a previous completed stroke or a plurality of these or combinations of these, but who does not currently have a stroke in progress is considered a subject at high risk for an ischemic condition, such as cerebral ischemia. Subjects having one or more other known risk factors, such as arterial hypertension, hypercholesterolemia, diabetes, smoking, auricular fibrillation, an embolic heart disease, or increasing are also considered at high risk of suffering an acute ischemic event such as stroke. For such at risk subject, the requirement is to provide a plasma level of a GPR109A agonist such that, on the occurrence of cerebral ischemia, there will be sufficient GPR109A agonist already present in the subject to protect neuronal cells, i.e., in an amount which would reduce neuronal cell death compared to that which would occur if a stroke occurred and was untreated. Administration of a GPR109 A agonist or of a pharmaceutically acceptable salt or solvate thereof is preferably carried out orally on a daily basis. [0471] The therapeutically effective amount for a subject who is at high risk for a stroke because of having experienced a previous ischemic event but who does not currently have a stroke in progress, is one that provides a plasma level of a GPR109A agonist such that on occurrence of cerebral ischemia there will be sufficient GPR109A agonist already present in the subject to protect neuronal cells, i.e., in an amount which will reduce neuronal cell death compared to that which would occur if a stroke occurred and was untreated. Since the occurrence of ischemia could come at any time, such plasma level must always be present, that is must be uninterrupted by reduction to a level where sufficient GPR109A agonist is not present to protect neuronal cells from death on the occurrence of ischemia. In general, this plasma level of a GPR109A agonist is a non-toxic concentration in the range of from about 0.01 μΜ to 1000 μΜ. The amount administered to obtain such plasma level depends on the method of administration and the half-life of the particular GPR109A agonist administered. Preferably, administration is on a daily basis so that each dose can be minimized. A suitable dose, orally administered, one time a day, is 50 mg/kg.

[0472] Subjects in need of the treatment according to the present invention are specially patients subjected to major surgery, e.g., patients who will undergo, are undergoing and in particular have undergone surgical operations in which hemorrhages, vascular manipulation or induced and maintained hypotension (neurosurgery, cardiovascular surgery, organ transplants, implant of orthopedic prosthesis, etc.) are likely to and in particular have occurred. In these cases, it is preferred to start treatment 24-48 hours before surgical operation at effective oral doses of e.g., 10-20 mg/day, 100-200 mg/day, or 1 -2 g/day. Drug administration is continued during surgical operation at effective doses of e.g. e.g., 10-20 mg/day, 100-200 mg/day, or 1-2 g/day by the intravenous route at the time of inducing anesthesia, and then for 1 week at effective doses of e.g. e.g., 10-20 mg/day, 100-200 mg/day, or 1-2 g/day by the oral or intravenous route depending on the patient's state.

[0473] For an at risk subject administration of a GPR109A agonist is preferably carried out orally so that the presence of a health care professional is not required.

F. Use Of A GPR109A Agonist In The Manufacture Of A Medicament

[0474] The present invention also provides for the use of a GPR 109 A agonist in the manufacture of a pharmaceutical composition or a medicament for the treatment of an ischemic condition. Ischemic conditions are described herein. Any GPR109A agonist described herein can be used in said manufacturing. [0475] In some embodiments of the present invention, the use of a GPR109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof is for the manufacture of a pharmaceutical composition or a medicament for the treatment or alleviation of cerebral ischemia.

[0476] In some embodiments of the present invention, the use of a GPR109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof is for the manufacture of a pharmaceutical composition or a medicament for the treatment or alleviation of an ischemic condition. The present invention also provides for the use of a GPR109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a pharmaceutical composition or a medicament for the prevention of an ischemic condition. Ischemic conditions are described herein. Any GPR109A agonist described herein can be used in said manufacturing.

[0477] In some embodiments of the present invention, the use of a GPR109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof is for the manufacture of a pharmaceutical composition or a medicament for the prevention of cerebral ischemia.

[0478] In some embodiments of the present invention, the use of a GPR109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof is for the manufacture of a pharmaceutical composition or a medicament for the treatment of a subject having a high risk for a stroke.

[0479] In some embodiments of the present invention, the use of a GPR 109A agonist or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof is for the manufacture of a pharmaceutical composition or a medicament for decreasing the severity of an infarct in a subject afflicted with cerebral ischemia.

[0480] While each of the elements of the present invention is described herein as containing multiple embodiments, it should be understood that, unless indicated otherwise, each of the embodiments of a given element of the present invention is capable of being used with each of the embodiments of the other elements of the present invention and each such use is intended to form a distinct embodiment of the present invention. Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0481] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0482] Throughout the present specification and the accompanying claims the words "comprise" and "include" and variations such as "comprises", "comprising", "includes" and "including" are to be interpreted inclusively. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows.

[0483] The referenced patents, patent applications, and scientific literature, including accession numbers to GenBank database sequences, referred to herein are hereby incorporated by reference in their entirety as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference. Any conflict between any reference cited herein and the specific teachings of this specification shall be resolved in favor of the latter. Likewise, any conflict between an art-understood definition of a word or phrase and a definition of the word or phrase as specifically taught in this specification shall be resolved in favor of the latter.

[0484] As can be appreciated from the disclosure above, the present invention has a wide variety of applications. The invention is further illustrated by the following examples, which are only illustrative and are not intended to limit the definition and scope of the invention in any way.

V. EXAMPLES

Example 1: General Material And Methods a) Chemicals

[0485] Nicotinic acid (pyridine-3-carboxylic acid) can be obtained from Sigma (St. Louis, MO). b) Radioligand Binding

[0486] Equilibrium binding of ³H-labeled nicotinic acid (50 Ci/mmol; American

Radiolabeled Chemicals, St. Louis, MO) is performed on 30 μg of membranes from human embryonic kidney 293T cells expressing wild-type or mutant GPR109A receptors in a total volume of 250 μΐ of binding buffer [50 mM Tris-HCI, pH 7.4, 2 mM MgCl₂, and 0.02% (v/v) CHAPS] as described previously (Tunaru et al, 2003,^' Nat Med 9:352-355). After 4 h of incubation at 25°C, unbound and membrane-bound radioactivity is separated by filtration of the samples through nitrocellulose filters, followed by two washing steps with 4 ml of ice- cold binding buffer. Nonspecific binding is determined in the presence of 200 μΜ unlabeled nicotinic acid. Equilibrium binding of other labeled GPR109A agonists can be done accordingly. c) Measurement of Adenylyl Cyclase Inhibition

[0487] A 96-well Adenylyl Cyclase Activation Flashplate Assay™ kit (e.g., PerkinElmer) is used to measure changes in intracellular cAMP levels due to receptor activation in CHO- l stable cell lines expressing GPR109A. CHO-K 1 cells are cultured in F- 12 aighn's modified cell culture medium with 10% fetal bovine serum, 2 mM l-glutamine, 1 mM sodium pyruvate, and 400

Geneticin in T- l 85 cell culture flasks. Cells are harvested from culture flasks and isolated via low speed centrifugation, counted, and diluted to a density of 1 x 10⁶ cells/ml. GPR109A agonist or candidate GPR109A agonist are prepared in Me₂SO and serially diluted with phosphate-buffered saline (PBS). Cells are added to the test plates containing the GPR109A agonist or candidate GPR109A agonist at a final cell density of 50,000 cells/well. 5 μηι forskolin is added to all wells. The assay plates are placed on a shaker for 1 h at room temperature (25°C). Diluted ¹²⁵I-cAMP is added to each well and the plates continued to shake for another 2 h. The plates are counted on a Wallac Microbeta Counter 1450.

d) MAP Kinase Assay

[0488] MAP kinase assays are performed using the phospho-MAP kinase enzyme-linked immunosorbent assay kit ( HO 0091 ) from BIOSOURCE according to the manufacturer's specifications. Specifically, CHO- 1 stable cell lines expressing GPR109A are serum- starved overnight. Cells are stimulated with GPR 109A agonist or candidate GPR109A agonist for 5 min at 37°C, the medium is aspirated, and the cells are rinsed with PBS. T e cells are scraped in 1 ml of PBS and transferred to a microfuge tube. The suspension is centrifuged for 5 min at 3000 rpm, and the pellet is resuspended in 200 μΐ of cell extraction buffer (0.1% SDS). The samples are incubated on ice for 30 min and then clarified by centrifugation for 10 min, 4°C at 13,000 rpm. Protein concentrations are determined by a modified Bradford analysis, and 10 μg of protein is added to each well of a 96- well plate coated with anti-phospho-MAP kinase capture antibody. The samples are incubated for 2 h at 25°C and then extensively washed before incubation with the anti-phospho-MAP kinase detection antibody for 1 h at 25°C. The samples are washed and then incubated with an horseradish peroxidase-conjugated secondary antibody for 30 min at 25°C. The samples are washed and then incubated with chromogen in the dark for 20 min at 25°C before stopping the reaction with stop buffer. Absorbance at 450 nm is read on a Spectramax 340PC microplate reader (Molecular Devices).

[0489] For the mouse ear MAP kinase assays, mice are injected intraperitoneal with either vehicle, GPR109A agonist or candidate GPR109A agonist at 100 mg/kg. After 5 min, mice are sacrificed via C0₂ asphyxiation and the ears removed. Ears are minced into small pieces and homogenized in lysis buffer using a Brinkman Polytron. Membrane protein is isolated via centrifugation at 20,000 rpm (JA-25.50 rotor, 15 min, 4°C). Membrane pellets are resuspended in 200 μΐ of cell extraction buffer and treated as described above.

e) Mouse Model for Ischemic Stroke

(0490J Male C57BL/6 mice and GPR109A knockout mice (Tunaru et ai, 2003, Nature Medicine 9: 352-355) are investigated at the age of 2 - 3 months. GPR 109A agonist or a candidate GPR109A agonist is dissolved in saline. The pH is adjusted to 7.4. The compounds are administered by intraperitoneal injection in a volume of 0.3 ml immediately before surgery, 4 h, 8 h, 24 h, 28 h, and 32 h after surgery. For surgery, mice are anesthetized by intraperitoneal injection of 150 μΐ 2.5% tribromoethanol per 10 g body weight. To occlude the middle cerebral artery (MCA) distally, a skin incision is made between the ear and the orbit on the left side. The temporal muscle is removed by electrical coagulation. The stem of the MCA is exposed through a burr hole and occluded by microbipolar coagulation (Erbe, Tubingen, Germany). Surgery is performed under a microscope (Hund, Wetzlar, Germany). A body temperature of 37°C is maintained by using a heating pad that is controlled by the rectal body temperature. Forty-eight hours after surgery, mice are deeply reanesthetized with tribromoethanol and perfused intracardially with Ringer's solution. Coronal cryosections of the brains (20 μηι in thickness) are cut every 400 μηι and stained with a silver technique. Infarct volumes are corrected for brain edema as has been described previously (Herrmann et al, 2005, Nat Med 1 1 : 1322-29). Surgery is performed and ischemic damage is measured by an investigator who preferably has no knowledge of the treatment group or the genotype. To determine blood pressure, glucose, and blood gases that may influence infarct volume, the femoral artery is cannulated in a separate cohort of animals. A blood sample of 100 μΐ is drawn 10 min before and 10 min after MCA occlusion (MCAO). For laser Doppler measurements, the probe (P415-205; Perimed) is placed 3 mm lateral and 6 mm posterior to the Bregma. Relative perfusion units are determined (Periflux 4001 ;

Perimed).

0 Bone Marrow Transplantation

[0491] Bone marrow is obtained aseptically from femurs and tibias of wild-type or GPRl 09 A knockout mice (Tunaru et ai, 2003, Nature Medicine 9: 352-355) after euthanizing animals by cervical dislocation. Unfractionated bone marrow cells is < resuspended in 0.25 ml sterile PBS and injected retro-orbitally into 10- to 13-week-old C57BL/6 or GPRl 09A knockout mice (Tunaru et ai, 2003, Nature Medicine 9: 352-355) that had been lethally irradiated (10 Gy) 1 d before. Six weeks after reconstituting the bone marrow, successful engraftment is confirmed by fluorescent activated cell sorting (FACS) analysis of GPR109A-expressing cells in blood. g) Fluorescence-Activated Cell Sorting (FACS) Analysis

[0492] FACS analysis of brain cells after occlusion of the middle cerebral artery was performed as described previously (Muhammad et al, 2008, J Neuroscience 28: 12023-

12031 ). Briefly, 48 hours after MCAO, mice were anesthetized by intraperitoneal injection of 200 μΐ of tribromoethanol per 10 g and perfused intracardially with Ringer's solution. The brain was freed from meninges, and the olfactory bulb and cerebellum was discarded. The separated hemispheres were homogenized in 1 x phosphate-buffered saline (PBS) containing bovine serum albumin (BSA) (0.2%), ethylenediaminetetraacetate (EDTA) (0.01 M), and DNAse 1 (10 mg/ml, Roche, Mannheim, Germany) and filtered through a 40-μηι nylon cell strainer (BD PharMingen, Erembodegem, Belgium). After centrifugation, cells from one hemisphere were resuspended in 5 ml of isotonic Percoll brought to a density of 1 .030 g/ml. This solution was underlayered with 2.5 ml of Percoll (1.095 g/ml), overlayered with 2.5 ml of Hank's balanced salt solution (HBSS) and centrifuged for 20 min at 1000 g at room temperature. Cells were collected from the top of the 1.095-g/ml layer, washed in 10 ml HBSS containing 10% fetal bovine serum (FBS), and counted in a Neubauer chamber. After treatment with purified rat anti-mouse CD16/32 (Fc Block, #553141 , BD Pharmingen) for 10 min on ice, cells were incubated with the following immunoglobulins (BD PharMingen) for 45 min on ice: PerCP-labeled rat anti-CD45 antibody (#557235), PerCP-labeled rat IgG2b, isotype control (#552991 ), PE-labeled rat anti-CD 1 l b antibody (#557397), PE-labeled rat IgG isotype control (#553989), PE-labeled rat anti-Ly-6G (#551461 ), PE-labeled rat isotype control IgG_2a,K (#553930), PE-labeled rat anti-CD3 (#555275), PE-labeled mouse anti-N -1 .1 (#557391 ), and PE-labeled mouse IgG_2a,K isotype control (#553457). Stained cells were quantified by FACS using FACS Calibur.

h) Determination Of Neurological Deficits

(1) Gait

[0493] After experiencing stroke, patients often suffer from gait disorders. The same phenomenon is observed in mice. Gait in the mice can be analyzed by three different methods (i) The paw-inking method, (ii) the catwalk overground gait analysis, and (iii) the DigiGait treadmill gait analysis.

[0494] The paw-inking method: the front paws of mice are labeled with nontoxic ink (Faber, Neumarkt, Germany). Mice are placed in front of a dark tunnel (length 30 cm, width 10 cm), the bottom surface of which is lined with white paper. Three to four strides are analyzed to determine stride length, step angle, stance width, and variability of stride length (the longest minus the shortest stride length).

[0495] Catwalk overground gait analysis: Mice are studied in a dark room (< 20 lux of illumination). The apparatus consists of an elevated, 1.3-m-long glass plate with dim fluorescent light beamed into the glass from the side. The light is reflected downwards and the images of the footprints are captured by a high-speed digital video camera positioned under the walkway when the animal's paws make contact with the glass surface (Noldus Information Technology, Wageningen, The Netherlands). The mice walk spontaneously at their own speed. Only uninterrupted runs are saved for analysis. Gait parameters are generated after each footprint is identified and labeled.

[0496] The DigiGait treadmill gait analysis system: ventral plane videography is applied to generate digital paw prints from which indices of gait were determined, as previously described (Hampton et al., 2004, Phsiol Behav 82:381 -389). Briefly, mice walk on a motor- driven treadmill with a transparent treadmill belt. The treadmill belt speed is set to 24 cm/s for all of the mice. Mice are trained to treadmill walking immediately before the test period. An acrylic compartment, ~5 cm or -10 cm wide by -25 cm long, the length of which is adjustable, is attached on top of the treadmill to keep the mice within the view of the camera while walking on the treadmill belt (DigiGait, Mouse Specifics, Inc., Boston, MA). Digital video images of the underside of the animals are captured at 150 frames per second. Plotting the area of each digital paw print (paw contact area) imaged sequentially in time provides a dynamic gait signal, representing the temporal record of paw placement relative to the treadmill belt. Multiple postural and kinematic metrics from the gait signals are determined.

(2) Corner Test

[0497] Sensorimotor function (e.g., orientation in space) is tested in mice using the corner test (Schallert et al. , 1982, Pharmacol Biochem Behav 16:455-462; Zhang et al., 2002, J Neurosci Methods 1 1 7:207-214)). The test device consists of two vertical boards (each 30 x 20 x 1 cm) attached on one side at an angle of 30°. A food pellet in a small opening between the two boards encourages the mice to enter the corner. The mice rear on their hindlimbs and turn to the right or left side after reaching the corner. Turns were only recorded if mice fully rose on their hindlimbs. A total of 12 turns were counted. The laterality index (LI) was calculated according to the formula: LI = (turns to the left side - turns to the right side)/total number of turnings.

(3) Handedness Test

[0498] The handedness (testing the preference of a mouse to use the right or left front paw) of mice is determined using the paw preference test (Collins et al., 1968, J Hered 59:9-12). The device consists of a transparent plexiglass box (10.5 x 6 x 6 cm). One side of the box has a feeding opening of 0.9 cm in diameter that is equally accessible from the right or the left side. Mice are accustomed to food pellets (size 2, Bioserv Biotechnologies Inc., Frenchtown, NJ, USA) for 1 week before the first test on day - 1 . After 12 hours of fasting, mice are placed in the box and the food pellets are placed in front of the opening enabling the mice to reach the pellets using the right or left paw. Twenty paw reaches for food are observed and recorded for each mouse. The handedness index (HI) is calculated according to the formula: HI = (use of the left paw - use of right paw)/20.

(4) Latency To Move

[0499] To obtain insight into measuring apathy, a latency-to-move test is used. Mice are placed on a plate and the time to move one body length (7 cm) is recorded.

(5) Electrocardiography

[0500] To determine cardiovascular rhythms, electocardiograms (ECGs) are recorded noninvasively in conscious mice using, e.g., the ECGenie electrocardiography system (Mousespecifics, Inc., Boston, MA) as described previously (Chu et al., 2001 , BMC Physiol 1 :6). ECG signals were recorded passively from the underside of the animal's paws as it rested atop of a platform embedded with conductive electrodes. The electrodes were connected to a custom-designed amplifier and analog-to-digital converter. The signals were digitized at a sampling rate of 2 kHz. Data from continuous recordings of 20-30 ECG signals were used in the analyses. Heart rate variability metrics were determined in the time domain and in the frequency domain. ECGs were recorded 3 - 4 days after pdMCAO or sham surgery.

Example 2: The GPR109A Agonist Nicotinic Acid Reduced The Infarct

Volume In A Mouse Model Of Stroke

[0501] Male C57BL/6 mice at the age of 2-3 months were used. Mice were anesthetized by intraperitoneal injection of 150 2.5% tribromoethanol per 10 g body weight. To occlude the middle cerebral artery (MCA) distally, a skin incision was made between the ear and the orbit on the left side. The temporal muscle was removed by electrical coagulation. The stem of the MCA was exposed through a burr hole and occluded by microbipolar coagulation (Erbe, Tubingen, Germany). Surgery was performed under a microscope (Hund, Wetzlar, Germany). A body temperature of 37°C was maintained by using a heating pad that was controlled by the rectal body temperature. Forty-eight hours after surgery, mice were deeply reanesthetized with tribromoethanol and perfused intracardially with Ringer's solution. Coronal cryosections of the brains (20 μπι in thickness) were cut every 400 μπι and stained with a silver technique. Infarct volumes were corrected for brain edema as has been described previously (Herrmann et al. , 2005, Nat Med 1 1 :1322-9). Surgery was performed and ischemic damage was measured by an investigator who had no knowledge of the treatment group. Nicotinic acid was dissolved in saline and injected three time per day intraperitoneal ly on the first and second day after MCAO (immediately before MCAO and 4 h, 8 h, 24 h, 28 h, and 32 h after MCAO) in the doses indicated. Nicotinic acid was injected in a volume of 0.3 ml per mouse. Controls were injected with the vehicle only. In the first experiment, the effect of nicotinic acid in a dose of 200 mg/kg and vehicle-treatment was determined (Fig. 2 A). In the second experiment, the effect of nicotinic acid in doses of 150 mg/kg, 100 mg/kg and vehicle-treatment was determined (Fig. 2B). In a third experiment, the effect of nicotinic acid in a dose of 200 mg/kg, 50 mg/kg and vehicle-treatment was determined (Fig. 2C).

[0502] The results showed that nicotinic acid reduced the infarct volumes (severity of infarct) in doses of 50 mg/kg to 200 mg/kg (Fig. 2). The specificity of nicotinic acid and the therapeutic time window can be confirmed by investigating the effect of the nicotinic acid in GPR109A knockout mice. [0503] The GPR109A agonist nicotinic acid reduced the infarct volume in a mouse model of cerebral ischemia. In addition to nicotinic acid, other GPR109A agonists described herein, are a new therapeutic strategy for the treatment of stroke.

Example 3: The GPR109A Agonist Nicotinic Acid Reduced The

Number of CD45*'ⁱCD 11 b⁺ Macrophages In The Brain But

Had No Effect On Other Cell Populations

[0504] To elucidate the mechanism of how nicotinic acid affects ischemic brain damage, the number of immune cells in the ischemic brain were quantified. C57BL/6 male mice at the age of 2 - 3 months were used. Mice were subjected to an occlusion of the middle cerebral artery as described above in Example 2. FACS Analysis was performed with the FACS Calibur (BD, Heidelberg, Germany). Quantification of cell populations showed that 2 days after middle cerebral artery occlusion, nicotinic acid significantly reduced the number of CD45^hiCDl lb⁺ macrophages in the brain. CD45⁺CD3⁺ T cells, CD45¹⁰ CD1 l b⁺ microglia, CD45⁺Ly6G⁺ neutrophils or CD45⁺NK1.1⁺ NK cells were not affected by the treatment with nicotinic acid. The data are summarized in Table 1.

[0505] Table 1. FACS analysis of brain cells after nicotinic acid treatment.

Values are % of total cell number. Kl , 2, and 4 (mouse 3 died), mice treated with vehicle only. NA 1 -NA4, mice treated with nicotinic acid (NA) in a dose of 200 mg/kg before surgery and 4 h, 8 h, 24 h, 28 h and 32 h after surgery. RH, right hemisphere; LH, left hemisphere. [0506] This experiment showed that treatment with nicotinic acid reduced the number of ,CD45^h,CDl l b⁺ cells representing activated macrophages in the ischemic hemisphere. This finding is in line with the localization of the GPR109A receptor on macrophages and neutrophils. It can be concluded that by inhibiting the ischemia-induced inflammation, GPR109A agonists ameliorate ischemic brain damage.

Example 4: GPR109A Agonists Activate GPR109A

[0507] To demonstrate that GPR109A agonists work only by activating the GPR109A receptor their efficacy is investigated in GPR109A knockout mice (Tunaru et al., 2003, Nature Medicine 9: 352-355). In GPR109A knockout mice GPR109A agonists have no effect on the infarct size or the neurological deficit that is observed after a stroke. GPR109A mice at the age of 2-3 months are used. Mice are anesthetized by intraperitoneal injection of 150 ih 2.5% tribromoethanol per 10 g body weight. To occlude the middle cerebral artery (MCA) distally, a skin incision is made between the ear and the orbit on the left side. The temporal muscle is removed by electrical coagulation. The stem of the MCA is exposed through a burr hole and occluded by microbipolar coagulation (Erbe, Tubingen, Germany). Surgery is performed under a microscope (Hund, Wetzlar, Germany). A body temperature of 37°C is maintained by using a heating pad that is controlled by the rectal body temperature. Forty eight hours after surgery, mice are deeply reanesthetized with tribromoethanol and perfused intracardially with Ringer's solution. Coronal cryosections of the brains (20 μπι in thickness) are cut every 400 μηι and stained with a silver technique. Infarct volumes are corrected for brain edema as has been described previously (Herrmann et al., 2005, Nat Med 1 1 : 1322-9). Surgery is performed and ischemic damage is measured by an investigator who has no knowledge of the treatment group. GPR109A agonists are administered by ip- injection or other routes. Controls are injected with the vehicle only. The infarct size (severity of infarct) is measured after 2 days or at later time points. In addition, neurological deficits are determined as described herein.

Example 5: Imaging Of GPR109A⁺ Cells

[0508] A BAC transgenic mouse line in which the red fluorescent protein (RFP) is expressed in the GPR109A locus enabled the visualization of GPR109A⁺ cells. This mouse line can be used to determine whether GPR109A agonists interfere with the recruitment or activation of these cells. Immunohistochemistry showed that in these mice, RFP is expressed in CD1 l b⁺ microglia (Fig. 13 A), but not in GFAP⁺ astrocytes (Fig. 13B) or NeuN⁺ neurons (Fig. 13C).

Claims

WHAT IS CLAIMED IS: 1. A method for the treatment or alleviation of an ischemic condition in a subject, the method comprising the steps of:

(a) selecting a subject having an ischemic condition; and

wherein said ischemic condition is treated or alleviated.

2. The method according to claim 1 , wherein the ischemic condition results from coronary artery bypass graft surgery, cerebral ischemia, focal cerebral infarction, cerebral hemorrhage, hemorrhage infarction, hypertensive hemorrhage, intracranial vascular hemorrhage, subarachnoid hemorrhage, hypertensive encephalopathy, carotid stenosis or occlusion, cardiogenic thromboembolism, spinal stroke, spinal cord injury, atherosclerosis, vasculitis, macular degeneration, myocardial infarction, cardiac ischemia or supraventricular tachyarrhythmia.

3. The method according to claim 1 , wherein the ischemic condition is . cerebral ischemia.

4. The method according to claim 1, wherein the GPR109A agonist is a compound represented by Formula (I):

5. The method according to claim 1 , wherein the GPR109A agonist is a compound represented by Formula (II):

6. The method according to claim 1 , wherein the GPR109A agonist is a compound represented

7. The method according to claim 1, wherein the GPR109A agonist is a compound represented by Formula (IV):

wherein R is

8. The method according to claim 1 , wherein the GPR109A agonist is a compound represented by Formula (V):

wherein R is

larmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

9. The method according to claim 1 , wherein the GPR 109A agonist is a compound represented by Formula (VI):

10. The method according to claim 1 , wherein the GPR109A agonist is a compo

1 1. The method according to claim 1 , wherein the GPR109A agonist is a compound represented

12. The method according to claim 1, wherein the GPR109A agonist is a compound represented by Formula (IX):

13. The method according to claim 1 , wherein the GPR109A agonist is a compound represented by Formula (X):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative

14. The method according to claim 1, wherein the GPR109A agonist is a compound represented by Formula (XI):

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof..

15. The method according to claim 1 , wherein the GPR109A agonist is a compound represented by Formula (XII):

16. The method according to claim 1, wherein the GPR109A agonist is a compound represented by Formula (XIII):

Ri is Ph, vinyl, Ethyl, 1 -spiro, spirocyc, 1 -cyclopentenyl, 1 -cyclohexenyl, 3- pyrimidine. 4-pyrimidine, 2-furan, 2,5-diCl-Ph, 2,4-diF-Ph, 3,4-diF-Ph, 2,6-diF-Ph, 3,5-diF-Ph, 2-F-Ph, 4-F-Ph. 3-F-Ph, 3-Cl-Ph, 3-Br-Ph, 3-1-Ph, 3-Me-Ph, 3-Et-Ph, 3-CF₃-Ph, or 3-OMe-Ph; and

R.2 is Me, Et, indane, or lopetane

17. The method according to claim 1 , wherein the GPR 109A agonist is a compound represented by Formula (XIV):

Ri is 2-thienyl, 5-Cl-2-thienyl, 5-Me-2-thienyl, 4-Br-2thienyl, 4-Me-2-thienyl, 4- Br-5-Me-2-thienyl, 3-thienyl, 5-Cl-3-thienyl, 5-Br-3-thienyl, or 5-Me-3-thienyl.

18. The method according to claim 1 , wherein the GPR 109A agonist is a compound represented by Formula (XXI):

X represents a nitrogen or carbon atom;

Y represents C or N, such that when Y represents nitrogen, the nitrogen atom may be optionally substituted with H or R⁶ wherein: R⁶ represents Ci.₃alkyl optionally substituted with 1 -3 halo groups;

the dashed lines represent optional bonds;

when the dashed line to Z represents a bond that is absent, the dashed line to (Y)_p represents a.bond that is present and Z represents a group selected from OH, SH, H2, C0₂H and SO₃H;

each R⁴ is H or halo, or is selected from the group consisting of:

a) a phenyl or a 5-6 membered heteroaryl group containing 1 heteroatom selected from O, S and N, and optionally containing 1-3 additional N atoms, said phenyl and heteroaryl groups being optionally substituted with 1 -3 substituents, 1 -3 of which are halo, and 0-1 of which are selected from: OH, NH₂, Ci.₃alkyl, Ci_-3alkoxy, haloCi.₃alkyl and

haloC].₃alkoxy; and

(b)

optionally substituted with 1 -3 substituent groups, 1 -3 of which are halo atoms, and 0-1 of which are selected from the group consisting of: OH, OCu ₃alkyl, NH_2, NHCi_-3alkyl, N(Ci_-3alkyl)₂, CN, N0₂, Hetcy, phenyl and a 5-6 membered heteroaryl group containing 1 heteroatom selected from O, S and N, and optionally containing 1 -3 additional N atoms, said phenyl and heteroaryl groups being optionally substituted with 1-3 substituents, 1 -3 of which are halo, and 0- 1 of which are selected from: OH, NH₂, C|.₃alkyl, Ci. ₃alkoxy, haloC|.₃aIkyl and haloC|.₃alkoxy;

ring A represents a 6-10 membered aryl, a 5-13 membered heteroaryl or a partially aromatic heterocyclic group, said heteroaryl and partially aromatic heterocyclic group containing at least one heteroatom selected from O, S and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1 -3 additional N atoms, with up to 5 heteroatoms being present;

R² and R³ are independently H, Ci_-3alkyl, haloC|.₃alkyl, OCi.₃alkyl, haloCi. ₃alkoxy, OH, NH₂ or F;

n represents an integer of from 1 to 5;

each R¹ is H or is selected from the group consisting of:

a) halo, OH, C0₂H, CN, NH_2, S(O)₀.₂R^e wherein R^e represents Ci^alkyl or phenyl, said Ci^alkyl or phenyl being optionally substituted with 1 -3 substituent groups, 1 -3 of which are selected from halo and Ci.₃alkyl, and 1 -2 of which are selected from the group consisting of: OCi_-3alkyl, haloCi_-3alkyl, haloCi_-3alkoxy, OH, NH₂ and NHCi_-3alkyl;

b) Ci-6 alkyl and OCi^alkyl, said group being optionally substituted with 1 -3 groups, 1 -3 of which are halo and 1 -2 of which are selected from: OH, C0₂H, C0₂Ci- alkyl, C0₂C_Mhaloalkyl, OC0₂C_Malkyl, NH₂, NHC_Malkyl, N(C alkyl)₂, Hetcy and CN;

c) Hetcy, NHC alkyl and N(C|_4alkyl)₂, the alkyl portions of which are optionally substituted as set forth in (b) above;

d) C(0)NH₂, C(0)NHC_Malkyl, C(0)N(C_1-4alkyl)₂, C(0)Hetcy,

C(0)NHOC alkyl and C(0)N(C_Malkyl)(OC alkyl), the alkyl portions of which are optionally substituted as set forth in (b) above;

e) NR C(0)R", NR^'S0₂R", NR^'C0₂R" and NR^'C(0)NR^"R^"' wherein:

R represents H, Ci.₃alkyl or haloCi.₃alkyl,

R" represents (a) Ci-salkyl optionally substituted with 1 -4 groups, 0-4 of which are halo, and 0- 1 of which are selected from the group consisting of: OCi^alkyl, OH, C0₂H, C0₂C_Malkyl, C0₂C_Mhaloalkyl, OC0₂C alkyl, NH₂, NHCi.₄alkyl, N(C_Malkyl)2, CN, Hetcy, Aryl and HAR,

said Hetcy, Aryl and HAR being further optionally substituted with 1 -3 halo, Ci^alkyl, C^alkoxy, haloCi^alkyl and haloC alkoxy groups;

(b) Hetcy, Aryl or HAR, said Aryl and HAR being further optionally substituted with 1 -3 halo, Ci-₄alkyl, Ci^alkoxy, aloC al yl and haloCi^alkoxy groups;

and R'" representing H or R"; and

f) phenyl or a 5-6 membered heteroaryl or heterocyclic group attached at any available point and being optionally substituted with 1 -3 halo, C|.₃alkyl or haloC|.₃alkyl groups, or 1 -2 OC |.₃alkyl or haloOC|.₃alkyl groups, or 1 moiety selected from the group 73 consisting of:

74 i) OH; C0₂H; CN; NH₂ ; S(O)_0-2R^E wherein R^E is as described above;

75 ii) NHCi-4alkyl and N(Ci-4alkyl)₂, the alkyl portions of which are

76 optionally substituted with 1 -3 groups, 1 -3 of which are halo and 1 -2 of which are selected from:

77 OH, C0₂H, C0₂C_Malkyl, C0₂C haloalkyl, OC0₂C,_-4alkyl, NH₂, NHC,.₄alkyl, N(C alkyl)₂,

78 CN;

79 iii) C(0)NH₂, C(0)NHC_Malkyl, C(0)N(C alkyl)₂, C(0)NHOC alkyl

80 and C(0)N(C |.₄alkyl)(OC alkyl), the alkyl portions of which are optionally substituted as set

8 1 forth in (b) above; and

82 iv) NR^'C(0)R", NR^'S0₂R", NR^'C0₂R" and NR^'C(0)NR ^"R"' wherein R ,

83 R" and R are as described above.

1 19. The method according to claim 1 , wherein the GPR109A agonist is a

2 compound represented by Formula (XXXI):

4 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative

5 thereof; wherein:

6 R , is -CH₂CH₂0-, -C₃H₆-, -C₄H₈-, -C₃H₇, C₃H₇, C H₉, C, ,H₂₃, C₆H₅, 3-Cl-C₆H₄,

7 4-Cl-C₆H₄, 4-CH₃-C₆H₄, C₆H₅-CH₂, 4-Cl-C₆H₄-CH₂, 4-CH₃-C₆H₄-CH₂, 4-OCH₃-C₆H₄-CH₂, 3-

8 C1-C₆H₄-CH₂, C₆H₅-C₂H₄, or C₆H₅-C₃H₆; and

9 R₂ is H.

1 20. The method according to claim 1 , wherein the GPR1 09A agonist is a

2 compound represented by Formula (XXXVI):

4 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof; wherein:

Ri is H, ethyl, w-propyl, -butyl, e«/-n-butyl, w-pentane, «-hexane, cyclopropyl, cyclopentyl, Ph, 3-Me-Ph, 2-Me-Ph, 4-Cl-Ph, 4-F-Ph, 2,4-F-Ph, 2,5-F-Ph, 2-Cl-Ph, 3,4-F-Ph, 2,3-F-Ph, 2-F-Ph, 3-Cl-Ph, 3-F-Ph, 2,3,5-F-Ph, ent 2,3,5-F-Ph, or 3,5-F-Ph, and

R₂ is tetrazole.

21. The method according to claim 1 , wherein the GPR109A agonist is a compound represented by Formula (XXXVII):

22. The method according to claim 1, wherein the GPR109A agonist is a compound represented by Formula (XXXVIII):

Ri is H, methyl, ethyl, propyl, /-propyl, c-propyl, butyl, and

R2 is H or halogen.

23. The method according to claim 1 , wherein the GPR109A agonist is a compound represented by Formula (XXXXIV):

(CR⁶R⁷)_n

Y

R⁸

X is selected from the group consisting of: a single bond, O, N(R⁹)C(0), N(R⁹)C(0)0, OC(0)NR⁹, N(R⁹)C(0)NR¹⁰, NR⁹S0₂, and C(0)NR⁹ if m is 1 , 2, or 3;

R¹, R², and R³ are independently from each other selected from the group consisting of: hydrogen, halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, fluoro-lower- alkoxy, and cycloalkyl;

R\ R⁵, R⁶ and R⁷ are independently from each other selected from the group consisting of: hydrogen, fluoro, lower-alkyl, and fluoro-lower-alkyl; or alternatively, R⁴ and R⁵ are bound together to form a ring together with the carbon atom to which they are attached wherein— R⁴— R⁵— is— (CH2)2-6— , or R⁶ and R⁷ are bound together to form a ring together with the carbon atom to which they are attached wherein— R⁶— R⁷— is— (CH2)2-6— ;

R⁸ is aryl is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently from each other selected from the group consisting of: halogen, lower-alkyl, lower-alkoxy, fluoro-lower-alkyl, fluoro-lower-alkoxy, cycloalkyl, fluoro-cycloalkyl, cycloalkyl-oxy, C(0)OH, lower-alkoxy-C(O), NH₂C(0), N(H,lower-alkyl)C(0), N(lower-alkyl)₂C(0), OH, lower-alkyl-C(0)0, NH₂, N(H,tower-alkyl), N(lower-alkyl)₂, lower-alkyl-C(0)NH, lower-alkyl-C(0)N(lower-alkyl), NH₂S0₂, N(H,lower- alkyl)S0₂, N(lower-alkyl)₂S0₂, lower-alkyl-S0₂— NH, lower-alkyl-S0₂— (lower-alkyl), cyano, and phenyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, lower-alkyl, lower-alkoxy and fluoro-lower-alkyl;

m is 0, 1 , 2 or 3; and n is 0, 1 , 2, 3, 4, 5 or 6; wherein m+n is > 1 .

24. The method according to claim 1 , wherein the GPR 109 A agonist is a compound represented by Formula (XXXXV):

R¹ represents hydrogen, halogen or Ci-C₃alkyl;

R² represents a 6 or 10-member aryl or heteroaryl ring system;

W represents a linker selected from:— C(R³R⁴)— {CH₂)„— ,— C(R³R⁴)—

(CH₂)„NHC(0)— ,— C(R³R⁴)— {CH₂)„NHC(0)NH— ,— C(R³R⁴)— (CH₂)_nNHC(0)0— , — C(R³R⁴)— (CH₂)„S0₂NR5³— ,— C(R³R⁴)— (CH₂)„NR⁵S0₂— ,— C(R³R⁴)— (CH₂)„0— , — C(R³R⁴>-<CH₂)„C(0)— ,— C(R³R⁴) ,— C(R³R⁴)— <CH₂)„S— ,

— C(R³R⁴)— (CH₂)„0— CH₂— ,

or (ΟΗ₂ ⁾, χ A . V represents CH or N;

A represents a linker selected from:— C(R³R⁴)— {CH₂)„— ,— C(R³R⁴)— (CH₂)„0— ,— C(R³R⁴)— (CH₂)„NH— , or— (R³R⁴)— (CH₂)„S— ;

n represents an integer selected from 0, 1 and 2;

R³ represents hydrogen, Ci-C₅alkyl, C₂-C₅alkenyl, C₅-C₆aryl or C₅-C₆cycloalkyl; R⁴ represents, Ci-C₅alkyl, C₂-C₅alkenyl, C₅-C₆aryl or C₅-C₆cycloalkyl or R³ and R⁴ together with the carbon atom to which they are attached form a 4, 5, 6 or 7-member cycloalkyl ring; and

R⁵ represents hydrogen or Ci-C₃alkyl 25. The method according to claim 1 , further comprising the step of:

(c) administering to said subject

(ii) a compound that enhances the neurotrophic activity of (i). 26. The method according to claim 1 , further comprising the step of:

(c) administering to said subject

(i) a lipid modifying compound; or

(ii) an active agent. 27. A method for treating a subject having a high risk for a stroke, the method comprising the steps of:

(a) selecting a subject having a high risk for a stroke; and

(b) administering to said subject a therapeutically effective amount of a G- protein coupled receptor 109A (GPR109A) agonist or a pharmaceutically acceptable salt or solvate thereof. 28. The method according to claim 27, wherein the subject has experienced a prior ischemic event. 29. The method according to claim 27, wherein the subject has one or more risk factor selected from the group consisting of arterial hypertension, hypercholesterolemia, diabetes, smoking, auricular fibrillation, an embolic heart disease, and increasing age. 30. A method for decreasing the severity of an infarct in a subject afflicted with a cerebral ischemia, the method comprising the steps of:

(a) selecting a subject having a cerebral ischemia;

(b) determining the severity of an infarct; and

(c) administering to said subject a therapeutically effective amount of a G-protein coupled receptor 109 A (GPR 109A) agonist or a pharmaceutically acceptable salt or solvate thereof,

wherein said severity of the infarct is decreased.