Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/26—Glucagons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

• the field of the present disclosure relates to methods, treatments and materials for treating diseases or disorders related to decreased circulating levels of glucagon and subsequent loss of direct and indirect beneficial effects on end organs including the heart and kidneys.
• This disclosure provides for methods of treating such diseases and disorders with a PDE1 inhibitor to slow cyclic nucleotide hydrolysis in combination with therapeutic agents that modulate circulating levels of glucagon or modulate glucagon receptor activity and directly or indirectly increase intracellular levels of cAMP.
• PDEs phosphodiesterases
• CaM-PDEs Ca2+/calmodulin-dependent phosphodiesterases
• PDE1A is expressed in the brain, lung, kidney and heart.
• PDE1B is primarily expressed in the central nervous system, but it is also detected in monocytes and neutrophils and has been shown to be involved in inflammatory responses of these cells.
• PDE1C is expressed in olfactory epithelium, cerebellar granule cells, striatum, kidney, heart, and vascular smooth muscle. PDE1C has been demonstrated to be a major regulator of proliferation and function in human smooth muscle.
• Cyclic nucleotide phosphodiesterases down-regulate intracellular cAMP and cGMP signaling by hydrolyzing these cyclic nucleotides to their respective 5’ -monophosphates (5’ AMP and 5’GMP), which are inactive in terms of intra-cellular signaling pathways.
• cAMP and cGMP are central intracellular second-messengers and they play roles in regulating numerous cellular functions.
• PDE1 A and PDE1B preferentially hydrolyze cGMP over cAMP, while PDE1C shows approximately equal cGMP and cAMP hydrolysis.
• a major component of cardiac dysfunction in heart failure resides in second messenger signaling defects coupled to cyclic 3', 5'-cyclic adenosine and guanosine monophosphate (cAMP, cGMP) that limit functional reserve.
• Cyclic AMP stimulates protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), acutely enhancing excitation- contraction coupling and sarcomere function.
• Cyclic GMP acts as a brake on this signaling by activating protein kinase G.
• Both cyclic nucleotides have relevant vascular and fibroblast activity, reducing vessel tone, altering permeability and proliferation, and suppressing fibrosis.
• PDE1 activity is believed to be altered in chronic disease conditions such as diabetes mellitus, atherosclerosis, cardiac pressure-load stress and heart failure, as well as in response to long-term exposure to nitrates.
• PDE1 A is highly upregulated after stimulation with ATII and TGFp Moreover, PDE1 inhibitors have been reported to decrease ATII or TGFp induced cardiac myofibroblast activation, ECM production, and profibrotic gene expression, suggesting that PDE1 inhibition also mediates the antifibrotic effects via cAMP.
• the PDE1 isozymes are also abundant in the kidney. Thus, it follows that increased cAMP levels induced by specific PDE1 inhibitors could be beneficial in treating renal diseases.
• kidney fibrosis is an important factor for the progression of kidney diseases, such as diabetes mellitus induced kidney failure, glomerulosclerosis and nephritis resulting in chronic kidney disease or end-stage renal disease.
• Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) have been implicated to suppress several known renal diseases through a number of complex mechanisms, such as the nitric oxide/ ANP/guanylyl cyclases/cGMP-dependent protein kinase and cAMP/Epac/adenylyl cyclases/cAMP-dependent protein kinase pathways. From these diverse mechanisms it has been proposed that new pharmacological treatments will evolve for the therapy or even prevention of kidney failure.
• glucagon A robust association exists between diabetes mellitus (DM) and certain diseases including heart failure and kidney disease. Increased levels of glucagon in DM have been considered deleterious because of alterations in its counterregulatory role to insulin.
• glucagon physiological role is broad and glucagon plays an important role in the maintenance of organs expressing glucagon receptor as both in heart and kidney.
• glucagon has been shown to be therapeutically useful in treating heart failure and to increase cardiac index and cardiac output while decreasing vascular resistance. These effects are thought to be mediated by glucagon receptor activation and subsequent increases in intracellular cyclic AMP signaling in the heart.
• glucagon induces vasodilation, and increases renal plasma flow, glomerular filtration rate and electrolyte excretion.
• DM sodium glucose co-transporter 2
• SGLT2 sodium glucose co-transporter 2
• other DM treatments for example the dipeptidyl peptidase-4 inhibitors, decrease glucagon and have raised concerns that their use may precipitate heart failure. Therefore, it is important to isolate glucagon’s hemodynamic action from its effects on glucose control.
• hemodynamic actions of SGLT2 inhibitors have been proposed to be independent of effects on glucose control and may act indirectly on the heart via increased glucagon secretion to alter myocardial metabolism, ion transporters, fibrosis, adipokines, and vascular function. These actions also may be beneficial in the preservation of renal function as well.
• glucagon e.g., glucagon, SGLT2 inhibitors or other agents that may directly or indirectly increase circulating glucagon in plasma.
• at least one PDE1 inhibitor to enhance and maintain glucagon receptor mediated increases in intracellular cAMP and at least one agent that modulates circulating glucagon levels or modulates glucagon receptor activity (e.g., glucagon, SGLT2 inhibitors or other agents that may directly or indirectly increase circulating glucagon in plasma).
• at least one PDE1 inhibitor to enhance and maintain glucagon receptor mediated increases in intracellular cAMP and at least one agent that modulates circulating glucagon levels or modulates glucagon receptor activity (e.g., glucagon, SGLT2 inhibitors or other agents that may directly or indirectly increase circulating glucagon in plasma).
• at least one agent that modulates circulating glucagon levels or modulates glucagon receptor activity e.g., glucagon, SGLT2 inhibitors or
• PDE1C is the predominant PDE1 isoform in cardiac tissue
• PDE1 inhibition has acute positive inotropic, lusitropic, and arterial vasodilatory effects via the ability of these inhibitors to enhance cyclic nucleotide signaling in the cardiovascular system.
• cyclic nucleotides, cAMP and cGMP play a prominent role in progressing renal disorders, such as, kidney fibrosis, chronic kidney disease, kidney fibrosis, renal failure, glomerulosclerosis and nephritis.
• Glucagon has historically been administered to treat heart failure. Glucagon administration can exert a positive action on cardiovascular performance by increasing cardiac index (cardiac output and contractility), and/or by decreasing peripheral vascular resistance. SGLT2 inhibitors also are known to elevate circulating levels of glucagon and have been found to exert an important role in the maintenance of both heart and kidney function.
• PDE1 inhibitors can be used in combination with glucagon or other agents that increase glucagon function to reduce the effective dose of the PDE1 inhibitor and/or the effective dose of the glucagon or glucagon modulating agent, for example a SGLT2 inhibitor, or to reduce the undesirable side effects of glucagon or glucagon modulating agent (e.g., mycotic infections, urinary tract infections, osmotic diuresis, and diabetic ketoacidosis).
• glucagon or glucagon modulating agent e.g., mycotic infections, urinary tract infections, osmotic diuresis, and diabetic ketoacidosis.
• the present disclosure provides a method for the treatment or prophylaxis of a disease, disorder or condition mediated by altered glucagon function, comprising administration of a pharmaceutically effective amount of a PDE1 inhibitor (e.g., a PDE1 inhibitor of Formula I, la, II, III, IV, V, VI and/or VII as herein described) and a pharmaceutically effective amount of a second active agent that increases circulating glucagon (e.g., SGLT2 inhibitor and/or glucagon) to a patient in need thereof.
• a PDE1 inhibitor e.g., a PDE1 inhibitor of Formula I, la, II, III, IV, V, VI and/or VII as herein described
• a second active agent that increases circulating glucagon
• the disease or condition mediated by altered glucagon function may be diabetes mellitus (e.g., type 2 diabetes mellitus), kidney fibrosis, chronic kidney disease, kidney fibrosis, renal failure, glomerulosclerosis, nephritis, heart failure (e.g., chronic heart failure, acute heart failure or heart failure consequent to myocardial infarction), angina, stroke, renal failure, essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension, congestive heart failure, an inflammatory disease or disorder, fibrosis, cardiac hypertrophy, vascular remodeling, a connective tissue disease or disorder (e.g., Marfan Syndrome), chronic heart failure, myocardial ischemia, myocardial hypoxia, reperfusion injury, left ventricular dysfunctions (e.g., myocardial infarction, ventricular expansion), vascular leakage (i.e., consequent
• the present disclosure provides for a combination therapy comprising a PDE1 inhibitor (e.g., a compound according to any of Formulas I, la, II, III, IV, V, VI and/or VII) and a second active agent that increases circulating glucagon (e.g., SGLT2 inhibitor and/or glucagon).
• a PDE1 inhibitor e.g., a compound according to any of Formulas I, la, II, III, IV, V, VI and/or VII
• a second active agent that increases circulating glucagon e.g., SGLT2 inhibitor and/or glucagon.
• Figure 1 illustrates the average change in cardiomyocyte sarcomere shortening upon co-administration of glucagon with a PDE1 inhibitor according to the present disclosure.
• Figure 2 illustrates the peak intracellular Ca2+ transient amplitude in cardiomyocytes upon co-administration of glucagon with a PDE1 inhibitor according to the present disclosure.
• the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are selective PDE1 inhibitors.
• PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are compounds of Formula I:
• Ri is H or Ci-4 alkyl (e.g., methyl);
• R4 is H or Ci-4 alkyl and R2 and R3 are, independently, H or Ci-4 alkyl
• R2 and R3 are both methyl, or R2 is H and R3 is isopropyl
• aryl e.g., R2 and R3 are both methyl, or R2 is H and R3 is isopropyl
• aryl e.g., R2 and R3 are both methyl, or R2 is H and R3 is isopropyl
• aryl e.g., R2 and R3 are both methyl, or R2 is H and R3 is isopropyl
• R2 is H and R3 and R4 together form a di-, tri- or tetramethylene bridge
• R5 is a substituted heteroarylalkyl, e.g., substituted with haloalkyl; or R5 is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A
• X, Y and Z are, independently, N or C, and Rs, R9, R11 and R12 are independently H or halogen (e.g., Cl or F), and Rio is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl) optionally substituted with halogen, or thiadiazolyl (e.g., l,2,3-thiadiazol-4- yl)), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methyl sulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, Rs, R9
• R6 is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), arylamino (e.g., phenylamino), heteroarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N- (arylalkyl)amino (e.g., N-phenyl-N-(l,r-biphen-4-ylmethyl)amino); and
• R13 and Ri4 are, independently, H or Ci-4 alkyl, aryl, heteroaryl, (optionally hetero) arylalkoxy or (optionally hetero)arylalkyl; in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates.
• PDE1 inhibitors for use in the methods as described herein are Formula la:
• R.2 and Rs are independently H or hydroxy and R3 and R.4 together form a tri- or tetra- methylene bridge [pref. with the carbons carrying R3 and R.4 having the R and S configuration respectively]; or R2 and R3 are each methyl and R4 and Rs are each H; or R2, R4 and R5 are H and R3 is isopropyl [pref. the carbon carrying R3 having the R configuration];
• R6 is (optionally halo- substituted) phenylamino, (optionally halo-substituted) benzylamino, Ci-4alkyl, or Ci-4alkyl sulfide; for example, phenylamino or 4- fluorophenylamino;
• (iii) Rio is Ci-4alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl (for example 6-fluoropyrid-2-yl), or thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl); and
• X and Y are independently C or N, in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates.
• PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are compounds of Formula
• X is Ci- 6 alkylene (e.g., methylene, ethylene or prop-2-yn-l-ylene);
• Y is a single bond, alkynylene (e.g., — CoC — ), arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene);
• alkynylene e.g., — CoC —
• arylene e.g., phenylene
• heteroarylene e.g., pyridylene
• Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl), halo (e.g., F, Br, Cl), haloCi- 6 alkyl (e.g., trifluoromethyl), — C(O) — R 1 , — N(R 2 )(R 3 ), or C3-7cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl);
• aryl e.g., phenyl
• heteroaryl e.g., pyridyl, e.g., pyrid-2-yl
• halo e.g., F, Br, Cl
• R 1 is Ci-6alkyl, haloCi-6alkyl, — OH or — OCi-6alkyl (e.g., — OCH3);
• R 2 and R 3 are independently H or Ci- 6 alkyl
• R 4 and R 5 are independently H, Ci- 6 alky or aryl (e.g., phenyl) optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl) or Ci- 6 alkoxy;
• halo e.g., fluorophenyl, e.g., 4-fluorophenyl
• hydroxy e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl
• Ci- 6 alkoxy e.g., Ci- 6 alkoxy
• X, Y and Z are independently and optionally substituted with one or more halo (e.g., F, Cl or Br), Ci- 6 alkyl (e.g., methyl), haloCi- 6 alkyl (e.g., trifluoromethyl), for example, Z is heteroaryl, e.g., pyridyl substituted with one or more halo (e.g., 6- fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4- fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloCi- 6 alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or Ci- 6 -alkyl (e.g., 5-methylpyrid-2-yl), or Z is aryl, e.g., phenyl, substituted with one or
• the present disclosure provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are Formula III: Formula III wherein
• R1 is H or Ci-4 alkyl (e.g., methyl or ethyl);
• III and R3 are independently H or Ci- 6 alkyl (e.g., methyl or ethyl);
• R4 is H or Ci-4 alkyl (e.g., methyl or ethyl);
• R6 and R7 are independently H or aryl (e.g., phenyl) optionally substituted with one or more groups independently selected from Ci- 6 alkyl (e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example unsubstituted phenyl or phenyl substituted with one or more halogen (e.g., F) or phenyl substituted with one or more Ci- 6 alkyl and one or more halogen or phenyl substituted with one Ci- 6 alkyl and one halogen, for example 4- fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl; and
• n is 1, 2, 3, or 4, in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates.
• the present disclosure provides that the PDE1 inhibitors for use in the methods of treatment and prophylaxis described herein are Formula IV wherein (i) Ri is Ci-4alkyl (e.g., methyl or ethyl), or -NH(R2), wherein R2 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;
• Ri Ci-4alkyl (e.g., methyl or ethyl), or -NH(R2), wherein R2 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;
• X, Y and Z are, independently, N or C;
• R3, R4 and Rs are independently H or Ci-4alkyl (e.g., methyl); or R3 is H and R4 and Rs together form a tri-methylene bridge (pref. wherein the R4 and Rs together have the cis configuration, e.g., where the carbons carrying R4 and Rs have the R and S configurations, respectively),
• R6, R7 and Rx are independently:
• Ci-4alkyl e.g., methyl
• pyrid-2-yl substituted with hydroxy or
• R6, R7 and/or Rx are not present; and when X, Y and Z are all C, then at least one of R6, R7 or Rx is -S(0)2-NH2 or pyrid-2-yl substituted with hydroxy, in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates.
• PDE1 inhibitors for use in the methods as described herein are Formula V: wherein
• Ri is -NH(R4), wherein R4 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;
• R2 is H or Ci- 6 alkyl (e.g., methyl, isobutyl or neopentyl);
• R3 is -SO2NH2 or -COOH; in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates.
• PDE1 inhibitors for use in the methods as described herein are Formula VI: wherein
• Ri is -NH(R4), wherein R4 is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;
• halo e.g., fluoro
• R2 is H or Ci- 6 alkyl (e.g., methyl or ethyl);
• R3 is H, halogen (e.g., bromo), Ci- 6 alkyl (e.g., methyl), aryl optionally substituted with halogen (e.g., 4-fluorophenyl), heteroaryl optionally substituted with halogen (e.g., 6-fluoropyrid-2-yl or pyrid-2-yl), or acyl (e.g., acetyl), in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates.
• halogen e.g., bromo
• Ci- 6 alkyl e.g., methyl
• aryl optionally substituted with halogen e.g., 4-fluorophenyl
• heteroaryl optionally substituted with halogen e.g., 6-fluoropyrid-2-yl or pyrid-2-yl
• acyl e.g., acetyl
• PDE1 inhibitors for use in the methods as described herein are Formula VII:
• Ri is -NH(R5), wherein Rs is phenyl optionally substituted with halo (e.g., fluoro), for example, 4-fluorophenyl;
• halo e.g., fluoro
• R2 and R3 are each independently H or Ci- 6 alkyl (e.g., methyl or ethyl);
• R4 is aryl optionally substituted with halogen (e.g., 4-fluorophenyl) or heteroaryl optionally substituted with halogen (e.g., 6-fluoropyrid-2-yl), in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates.
• halogen e.g., 4-fluorophenyl
• heteroaryl optionally substituted with halogen e.g., 6-fluoropyrid-2-yl
• the present disclosure provides for administration of a PDE1 inhibitor for use in the methods described herein (e.g., a compound according to Formulas I, la, II, III, IV, V, VI and/or VII), wherein the inhibitor is a compound according to the following:
• the present disclosure provides administration of a PDE1 inhibitor for use in the methods described herein, wherein the inhibitor is a compound according to the following: in free or pharmaceutically acceptable salt form.
• the present disclosure provides administration of a PDE1 inhibitor for use in the methods described herein, wherein the inhibitor is a compound according to the following:
• the present disclosure provides administration of a
• PDE1 inhibitor for use in the methods described herein, wherein the inhibitor is a compound according to the following: in free or pharmaceutically acceptable salt form.
• the present disclosure provides administration of a
• PDE1 inhibitor for use in the methods described herein, wherein the inhibitor is a compound according to the following:
• the present disclosure provides administration of a
• PDE1 inhibitor for use in the methods described herein, wherein the inhibitor is a compound according to the following: in free or pharmaceutically acceptable salt form.
• Formulas I, la, II, III, IV, V, VI and/or VII are compounds that inhibit phosphodiesterase- mediated (e.g., PDE1 -mediated, especially PDElB-mediated) hydrolysis of cGMP, e.g., the preferred compounds have an IC50 of less than ImM, preferably less than 500 nM, preferably less than 50 nM, and preferably less than 5nM in an immobilized-metal affinity particle reagent PDE assay, in free or salt form.
• the present disclosure provides administration of a PDE1 inhibitor for treatment according to the methods described herein, wherein the inhibitor is a compound according to the following: [0034] Further examples of PDE1 inhibitors suitable for use in the methods and treatments discussed herein can be found in International Publication WO2006133261 A2; U.S. Patent 8,273,750; U.S. Patent 9,000,001; U.S. Patent 9,624,230; International Publication W02009075784A1; U.S. Patent 8,273,751; U.S. Patent 8,829,008; U.S. Patent 9,403,836; International Publication W02014151409A1, U.S. Patent 9,073,936; U.S.
• Patent 9,598,426 U.S. Patent 9,556,186; U.S. Publication 2017/0231994A1, International Publication WO2016022893A1, and U.S. Publication 2017/0226117A1, each of which are incorporated by reference in their entirety.
• PDE1 inhibitors suitable for use in the methods and treatments discussed herein can be found in International Publication W02018007249A1; U.S. Publication 2018/0000786; International Publication WO2015118097A1; U.S. Patent 9,718,832; International Publication W02015091805A1; U.S. Patent 9,701,665; U.S. Publication 2015/0175584A1; U.S. Publication 2017/0267664A1; International Publication WO2016055618A1; U.S. Publication 2017/0298072A1; International Publication W02016170064A1; U.S.
• Selective PDE1 inhibitor refers to a PDE1 inhibitor with at least 100-fold selectivity for PDE1 inhibition over inhibition of any other PDE isoform.
• Alkyl as used herein is a saturated or unsaturated hydrocarbon moiety, preferably saturated, preferably having one to six carbon atoms, which may be linear or branched, and may be optionally mono-, di- or tri- substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy.
• halogen e.g., chloro or fluoro
• Cycloalkyl as used herein is a saturated or unsaturated nonaromatic hydrocarbon moiety, preferably saturated, preferably comprising three to nine carbon atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, and which may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy.
• halogen e.g., chloro or fluoro
• the cycloalkyl optionally contains one or more atoms selected from N and O and/or S, said cycloalkyl may also be a heterocycloalkyl.
• Heterocycloalkyl is, unless otherwise indicated, saturated or unsaturated nonaromatic hydrocarbon moiety, preferably saturated, preferably comprising three to nine carbon atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, wherein at least one carbon atom is replaced with N, O or S, which heterocycloalkyl may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy.
• halogen e.g., chloro or fluoro
• Aryl as used herein is a mono or bicyclic aromatic hydrocarbon, preferably phenyl, optionally substituted, e.g., with alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloalkyl (e.g., trifluoromethyl), hydroxy, carboxy, or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl).
• alkyl e.g., methyl
• halogen e.g., chloro or fluoro
• haloalkyl e.g., trifluoromethyl
• hydroxy carboxy
• an additional aryl or heteroaryl e.g., biphenyl or pyridylphenyl
• Heteroaryl as used herein is an aromatic moiety wherein one or more of the atoms making up the aromatic ring is sulfur or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl, which may be optionally substituted, e.g., with alkyl, halogen, haloalkyl, hydroxy or carboxy.
• Compounds of the Disclosure may exist in free or salt form, e.g., as acid addition salts.
• language such as “Compounds of the Disclosure” is to be understood as embracing the compounds in any form, for example free or acid addition salt form, or where the compounds contain acidic substituents, in base addition salt form.
• the Compounds of the Disclosure are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Disclosure or their pharmaceutically acceptable salts, are therefore also included.
• Compounds of the Disclosure may in some cases also exist in prodrug form.
• a prodrug form is compound which converts in the body to a Compound of the Disclosure.
• these substituents may form physiologically hydrolysable and acceptable esters.
• physiologically hydrolysable and acceptable ester means esters of Compounds of the Disclosure which are hydrolysable under physiological conditions to yield acids (in the case of Compounds of the Disclosure which have hydroxy substituents) or alcohols (in the case of Compounds of the Disclosure which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered.
• the Compound of the Disclosure contains a hydroxy group, for example, Compound-OH
• the acyl ester prodrug of such compound i.e., Compound-0-C(0)-Ci-4alkyl
• the Compound of the Disclosure contains a carboxylic acid, for example, Compound-C(0)OH, the acid ester prodrug of such compound, Compound-C(0)0-Cl-4alkyl can hydrolyze to form Compound-C(0)OH and HO-Cl-4alkyl.
• the disclosure further provides a pharmaceutical composition comprising a PDE1 inhibitor in combination with an agent that increases circulating glucagon (e.g., glucagon and/or sodium glucose cotransporter 2 (SGLT2) inhibitor), each in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable carrier.
• an agent that increases circulating glucagon e.g., glucagon and/or sodium glucose cotransporter 2 (SGLT2) inhibitor
• SGLT2 sodium glucose cotransporter 2
• the disclosure provides a pharmaceutical composition containing such a compound.
• the combination of the PDE1 inhibitor and the agent that increases circulating glucagon allows the agent to be administered in a dosage lower than would be effective if administered as sole monotherapy.
• the disclosure further provides a pharmaceutical composition
• a pharmaceutical composition comprising a Compound of the Disclosure, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable carrier.
• the disclosure further provides a pharmaceutical composition
• a pharmaceutical composition comprising a Compound of the Disclosure, in free, pharmaceutically acceptable salt or prodrug form, in admixture with a pharmaceutically acceptable carrier.
• the Compounds of the Disclosure may be modified to affect their rate of metabolism, e.g., to increase half-life in vivo.
• the compounds may be deuterated or fluorinated to reduce the rate of metabolism of the compounds disclosed herein.
• the compounds disclosed herein may be in the form of a pharmaceutical composition, for example for oral administration, e.g., in the form of tablets or capsules, or for parenteral administration.
• the compounds are provided in the form of a long acting depot composition for administration by injection to provide sustained release.
• the solid drug for oral administration or as a depot may be in a suitable polymer matrix to provide delayed release of the active compound.
• the Compounds of the Disclosure and their pharmaceutically acceptable salts may be made using the methods as described and exemplified herein and by methods similar thereto and by methods known in the chemical art.
• the Compounds of the Disclosure include their enantiomers, diastereoisomers and racemates, as well as their polymorphs, hydrates, solvates and complexes.
• Some individual compounds within the scope of this disclosure may contain double bonds. Representations of double bonds in this disclosure are meant to include both the E and the Z isomer of the double bond.
• some compounds within the scope of this disclosure may contain one or more asymmetric centers. This disclosure includes the use of any of the optically pure stereoisomers as well as any combination of stereoisomers.
• the Compounds of the Disclosure encompass their stable and unstable isotopes.
• Stable isotopes are nonradioactive isotopes which contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). It is expected that the activity of compounds comprising such isotopes would be retained, and such compound would also have utility for measuring pharmacokinetics of the non-isotopic analogs.
• the hydrogen atom at a certain position on the Compounds of the Disclosure may be replaced with deuterium (a stable isotope which is non-radioactive). Examples of known stable isotopes include, but not limited to, deuterium, 13 C, 15 N, 18 O.
• unstable isotopes which are radioactive isotopes which contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g., 123 1, 131 I, 125 I, U C, 18 F, may replace the corresponding abundant species of I, C and F.
• Another example of useful isotope of the compound of the disclosure is the U C isotope.
• the present disclosure further provides for inhibitors of sodium glucose cotransporter 2 (SGLT2).
• SGLT2 inhibitors are known, of a variety of chemical structures.
• the SGLT2 inhibitors of the present disclosure include atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, and phlorizin.
• the SGLT2 inhibitors employed in the present disclosure are selective for SGLT2 relative to SGLT1, e.g., dapagliflozin.
• SGLT2 inhibitors suitable for use in accordance with the present disclosure comprise C-arylglucosides or O-arylglucosides. C- arylglucosides and O-arylglucosides are effective in treating diabetes. See U.S. Pat. No.
• C-arylglucoside (also referred to as C-glucosides) SGLT2 inhibitors which can be employed in the methods of the disclosure, include those disclosed in U.S. Patents 6,515,117, 6,414,126, and 6,774,112, as well as U.S. Publications US2006/0063722, US2005/0209166, and US2006/0074031, the disclosures of each of which are incorporated herein by reference in their entireties.
• O-glucoside SGLT2 inhibitors which can be employed in the methods of the disclosure include those disclosed in U.S. Patents 6,908,905 and 6,815,428, U.S.
• the present disclosure provides SGLT2 inhibitors for use in the methods of the disclosure that are disclosed in U.S. Pat. Nos. 6,414,126 and 6,515,117, e.g., the SGLT2 inhibitor is dapagliflozin
• the disclosure provides crystalline forms of compound I including the crystalline forms disclosed in U.S. Patent Application Publication No. 2008/0004336, the disclosure of which is incorporated herein by reference in its entirety.
• Additional SGLT2 inhibitors that may be employed in the present disclosure include canagliflozin (Johnson & Johnson/Mitsubishi Tanabe Pharma); remogliflozin etabonate (Islet Sciences, Kissei Pharmaceuticals Co.); ipragliflozin (Astellas/Kotobuki); empagliflozin (Boehringer Ingelheim); BI-44847 (Boehringer Ingelheim); TS-071 (Taisho Pharmaceutical); tofogliflozin (Roche/Chugai Pharmaceutical); LX-4211 (Lexicon Pharmaceuticals); DSP-3235 (GlaxoSmithKline/Dainippon Sumitomo); ISIS-SGLT2Rx (Isis Pharmaceuticals); and YM543 (Astellas Pharma Inc).
• a further SGLT-2 inhibitor is ertugliflozin (Pfizer and Merck).
• prodrugs are known in the art. Examples of such prodrugs are disclosed in, for example, Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991); and H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
• Examples of such prodrugs are in vivo cleavable esters of a compound of the disclosure.
• An in vivo cleavable ester of a compound of the disclosure containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid.
• Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters, for example methyl or ethyl; (l-6C)alkoxymethyl esters, for example methoxymethyl; (l-6C)alkanoyloxymethyl esters, for example pivaloyloxymethyl; phthalidyl esters; (3-8C)cycloalkoxycarbonyloxy(l-6C)alkyl esters, for example 1- cyclohexylcarbonyloxyethyl; l,3-dioxolan-2-ylmethyl esters, for example 5-methyl-l,3- dioxolan-2-ylmethyl; (l-6C)alkoxycarbonyloxy ethyl esters, for example 1- methoxycarbonyloxy ethyl; aminocarbonylmethyl esters and mono- or di-N-((l-6C)alkyl) versions thereof, for example N,N-dimethylaminocarbonylmethyl esters and N
• An in vivo cleavable ester of a compound of the disclosure containing a hydroxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent hydroxy group.
• Suitable pharmaceutically acceptable esters for hydroxy include (l-6C)alkanoyl esters, for example acetyl esters; and benzoyl esters wherein the phenyl group may be substituted with aminomethyl or N-substituted mono- or di-(l-6C)alkyl aminomethyl, for example 4-aminomethylbenzoyl esters and 4-N,N- dimethylaminomethylbenzoyl esters.
• the present disclosure provides a method [Method 1] for the treatment or prophylaxis of a disease, disorder or condition associated with altered glucagon function and/or altered cyclic nucleotides (e.g., cAMP and/or cGMP) signaling, comprising administration of a pharmaceutically effective amount of a PDE1 inhibitor (e.g., a PDE1 inhibitor of Formula I, la, II, III, IV, V, VI and/or VII as herein described) and a pharmaceutically effective amount of an agent that increases circulating glucagon levels or activates glucagon receptors (e.g., glucagon, SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) to a patient in need thereof.
• a PDE1 inhibitor e.g., a PDE1 inhibitor of Formula I, la, II, III, IV, V, VI and/or VII as herein described
• Method 1 wherein the disease, disorder or condition is associated with altered cyclic nucleotides (e.g., cAMP or cGMP) signaling.
• cyclic nucleotides e.g., cAMP or cGMP
• cyclic nucleotides e.g., cAMP and/or cGMP
• condition, disease or disorder is a cardiovascular condition, disease or disorder, a renal condition, disease or disorder, or a metabolic condition, disease or disorder.
• condition, disease or disorder is a cardiovascular condition, disease or disorder selected from angina, stroke, renal failure, essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension, congestive heart failure, an inflammatory disease or disorder, fibrosis (e.g., cardiac fibrosis associated with or induced by ventricular or supraventricular fibrillation), cardiac remodeling during gestation (i.e., peripartum cardiomyopathy), cardiac hypertrophy, vascular remodeling, a connective tissue disease or disorder (e.g., Marfan Syndrome), chronic heart failure, acute heart failure, heart failure consequent to myocardial infarction, myocardial ischemia, myocardial hypoxia, reperfusion injury, left ventricular dysfunctions (e.g., myocardial infarction, ventricular expansion), vascular leakage (i.e., consequent to hypoxia), muscular dystrophy (e.g.,
• any of the preceding methods, wherein the condition, disease or disorder is heart failure (e.g., chronic heart failure, acute heart failure, heart failure consequent to myocardial infarction, congestive heart failure).
• heart failure e.g., chronic heart failure, acute heart failure, heart failure consequent to myocardial infarction, congestive heart failure.
• the condition, disease or disorder is chronic heart failure.
• the condition, disease or disorder is acute heart failure.
• the condition, disease or disorder is heart failure consequent to myocardial infarction.
• the condition, disease or disorder is congestive heart failure.
• any of the preceding methods, wherein the condition, disease or disorder is hypertension (e.g., essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension). Any of the preceding methods, wherein the condition, disease or disorder is essential hypertension. Any of the preceding methods, wherein the condition, disease or disorder is pulmonary hypertension. Any of the preceding methods, wherein the condition, disease or disorder is secondary hypertension. Any of the preceding methods, wherein the condition, disease or disorder is isolated systolic hypertension. Any of the preceding methods, wherein the condition, disease or disorder is hypertension associated with diabetes.
• hypertension e.g., essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension.
• any of the preceding methods wherein the condition, disease or disorder is hypertension associated with atherosclerosis. Any of the preceding methods, wherein the condition, disease or disorder is renovascular hypertension. Any of the preceding methods, wherein the condition, disease or disorder is a renal condition, disease or disorder (e.g., kidney fibrosis, chronic kidney disease, renal failure, glomerulosclerosis and nephritis, a renal disorder consequent to diabetes, an injury to a kidney, high blood pressure, a cancerous growth (e.g., polycystic kidney disease)). Any of the preceding methods, wherein the condition, disease or disorder is kidney fibrosis. Any of the preceding methods, wherein the condition, disease or disorder is chronic kidney disease.
• a renal condition, disease or disorder e.g., kidney fibrosis, chronic kidney disease, renal failure, glomerulosclerosis and nephritis, a renal disorder consequent to diabetes, an injury to a kidney, high blood pressure, a cancerous growth
• any of the preceding methods, wherein the condition, disease or disorder is renal failure. Any of the preceding methods, wherein the condition, disease or disorder is a renal condition, disease or disorder consequent to diabetes mellitus. Any of the preceding methods, wherein the condition, disease or disorder is a metabolic disease, disorder or condition (e.g., type 1 diabetes mellitus, type 2 diabetes mellitus, high cholesterol, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, gestational diabetes, insulin resistance, conditions consequent to diabetes mellitus, e.g., cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease, degeneration or decline in the functionality of pancreatic beta cells, conditions consequent to an abnormal accumulation of ectopic fat, hyperinsulemia, new onset diabetes after transplantation
• any of the preceding methods, wherein the condition, disease or disorder is type 1 diabetes mellitus. Any of the preceding methods, wherein the condition, disease or disorder is type 2 diabetes mellitus. Any of the preceding methods, wherein the condition, disease or disorder is gestational diabetes. Any of the preceding methods, wherein the condition, disease or disorder is impaired glucose tolerance. Any of the preceding methods, wherein the condition, disease or disorder is hyperglycemia.
• condition, disease or disorder is a condition consequent to diabetes mellitus (e.g., cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease).
• the PDE1 inhibitor is administered at a concentration of 0.01 mg/kg to 100 mg/kg.
• the patient is a human and the PDE1 inhibitor is administered at an oral daily dosage of 1 - 300 mg.
• the PDE1 inhibitor is administered at a dosage of 1 mg, 3, mg, 10 mg, 30 mg, or 90 mg.
• any of the preceding methods wherein the agent that increases circulating glucagon levels or activates glucagon receptors (e.g., glucagon, SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) is administered at a dosage of 0.001 mg/kg to about 100 mg/kg body weight of the subject.
• the PDE1 inhibitor is administered orally.
• the PDE1 inhibitor is administered as a tablet or capsule.
• the PDE1 inhibitor is a compound according to any of Formulas I, la, II, III, IV, V, VI and/or VII.
• the PDE1 inhibitor is a compound according to Formula la.
• the PDE1 inhibitor is a compound according to:
• any of the preceding methods, wherein the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form. Any of the preceding methods, wherein the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form. Any of the preceding methods, wherein the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form. Any of the preceding methods, wherein the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form. Any of the preceding methods, wherein the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form. Any of the preceding methods, wherein the PDE1 inhibitor is a compound according to:
• the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form.
• the PDE1 inhibitor is administered at an oral daily dosage of 0.01-300mg, e.g., 1-90 mg, e.g., 1 mg,
• the PDE1 inhibitor is selected from a. (6ai?,9aN)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6- fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[l,2-a]pyrazolo[4,3- e]pyrimidin-4(2i )-one, in free or pharmaceutically acceptable salt form, e.g., monophosphate salt form; b.
• any of the preceding methods wherein the patient is a human. Any of the preceding methods, wherein the agent that modulates circulating glucagon levels or activates glucagon receptors is selected from glucagon, atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin (e.g., remogliflozin etabonate), sergliflozin (e.g., sergliflozin etabonate), sotagliflozin, tofogliflozin, and phlorizin, in free or pharmaceutically acceptable salt form.
• glucagon atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipraglifl
• any of the preceding methods wherein the agent that modulates circulating glucagon levels or activates glucagon receptors is selected from glucagon, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, in free or pharmaceutically acceptable salt form. Any of the preceding methods, wherein the agent that increases circulating glucagon levels or activates glucagon receptors is dapagliflozin, in free or pharmaceutically acceptable salt form. Any of the preceding methods, wherein the agent that increases circulating glucagon levels or activates glucagon receptors is dapagliflozin in free form.
• any of the preceding methods wherein the agent that increases circulating glucagon levels or activates glucagon receptors is glucagon. Any of the preceding methods, further comprising administering a pharmaceutically effective amount of a dipeptidyl peptidase-4 (DPP -4) inhibitor.
• DPP -4 dipeptidyl peptidase-4
• the DPP-4 inhibitor comprises sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and/or dutogliptin, in free or pharmaceutically acceptable salt form.
• the DPP-4 inhibitor comprises sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and/or dutogliptin, in free or pharmaceutically acceptable salt form.
• the disclosure further provides a PDE1 inhibitor and an agent that increases modulates glucagon levels or activates glucagon receptors (e.g., glucagon, SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) for use in a method of treating a disease, disorder or condition associated with altered glucagon function and/or a disease, disorder or condition mediated by altered cyclic nucleotides (e.g., cAMP and/or cGMP) signaling, e.g., for use in any of Methods 1, et seq.
• glucagon receptors e.g., glucagon, SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon
• the disclosure further provides the use of a combination therapy comprising or consisting of a PDE1 inhibitor and an agent that increases circulating glucagon levels or activates glucagon receptors (e.g., glucagon, SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) in the manufacture of a medicament for use in a method of treating a disease, disorder or condition associated with altered glucagon function and/or a disease, disorder or condition mediated by altered cyclic nucleotides (e.g., cAMP and/or cGMP) signaling, e.g., a medicament for use in any of Methods 1, et seq.
• a combination therapy comprising or consisting of a PDE1 inhibitor and an agent that increases circulating glucagon levels or activates glucagon receptors (e.g., glucagon, SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) in the manufacture of a medicament for use in a method of
• the disclosure further provides a pharmaceutical composition
• a PDE1 inhibitor e.g., any of a Compound of Formulas I, la, II, III, IV, V, VI and/or VII
• a pharmaceutically effective amount of an agent that increases circulating glucagon levels or activates glucagon receptors e.g., glucagon, SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon
• an agent that increases circulating glucagon levels or activates glucagon receptors e.g., glucagon, SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon
• the PDE1 inhibitor is administered in combination with other therapeutic modalities.
• a patient may be administered with agent that increases circulating glucagon levels or activates glucagon receptors (e.g., glucagon, SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon) in combination with any of the disclosed PDE1 inhibitors.
• agent that increases circulating glucagon levels or activates glucagon receptors e.g., glucagon, SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon
• Combinations may be achieved by administering a single composition or pharmacological formulation that includes the PDE1 inhibitor and one or more additional therapeutic agents, or by administration of two distinct compositions or formulations, separately, simultaneously or sequentially, wherein one composition includes the PDE1 inhibitor and the other includes the additional therapeutic agent or agents.
• the therapy using a PDE1 inhibitor may precede or follow administration of the other agent(s) by intervals ranging from minutes to weeks.
• the other agent and expression construct are applied separately to the cell, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the agent and expression construct would still be able to exert an advantageously combined effect on the cell.
• the present disclosure also provides for a pharmaceutical combination [Combination 1] therapy comprising a pharmaceutically effective amount of a PDE1 inhibitor (e.g., a compound according to any of Formula I, II, III, IV, V, VI and/or VII) and a pharmaceutically effective amount of an agent that increases circulating glucagon levels or activates glucagon receptors (e.g., glucagon, SGLT2 inhibitor or other agents that may directly or indirectly increase plasma glucagon), for administration in a method of treating a disease, disorder or condition associated with altered glucagon function and/or a disease, disorder or condition mediated by altered cyclic nucleotides (e.g., cAMP and/or cGMP) signaling, e.g., in accordance with any of Method 1, et seq.
• a PDE1 inhibitor e.g., a compound according to any of Formula I, II, III, IV, V, VI and/or VII
• any of the preceding combinations, wherein the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form. Any of the preceding combinations, wherein the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form. Any of the preceding combinations, wherein the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form. Any of the preceding combinations, wherein the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form. Any of the preceding combinations, wherein the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form. Any of the preceding combinations, wherein the PDE1 inhibitor is a compound according to:
• the PDE1 inhibitor is a compound according to: in free or pharmaceutically acceptable salt form.
• the PDE1 inhibitor is administered at an oral daily dosage of 0.01-300 mg, e.g., 1-90 mg, e.g., 1 mg, 3, mg, 10 mg, 30 mg, or 90 mg, and the PDE1 inhibitor is selected from a.
• glucagon atigliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflo
• any of the preceding combinations, wherein the agent that increases circulating glucagon levels or activates glucagon receptors is selected from glucagon, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, in free or pharmaceutically acceptable salt form. Any of the preceding combinations, wherein the agent that increases circulating glucagon levels or activates glucagon receptors is dapagliflozin, in free or pharmaceutically acceptable salt form. Any of the preceding combinations, wherein the agent that increases circulating glucagon levels or activates glucagon receptors is dapagliflozin in free form.
• any of the preceding combinations, wherein the agent that increases circulating glucagon levels or activates glucagon receptors is glucagon.
• the subject is suffering from a condition, disease or disorder which is mediated by cyclic nucleotides (e.g., cAMP or cGMP).
• cyclic nucleotides e.g., cAMP or cGMP
• sodium glucose cotransporter 2 SGLT2
• the DPP -4 inhibitor comprises sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and/or dutogliptin, in free or pharmaceutically acceptable salt form.
• PDE1 inhibitor as used herein describes a compound(s) which selectively inhibit phosphodiesterase-mediated (e.g., PDE1 -mediated) hydrolysis of cGMP and cAMP, e.g., with an IC50 of less than ImM, preferably less than 750 nM, more preferably less than 500 nM, more preferably less than 50 nM in an immobilized-metal affinity particle reagent PDE assay.
• IC50 of less than ImM, preferably less than 750 nM, more preferably less than 500 nM, more preferably less than 50 nM in an immobilized-metal affinity particle reagent PDE assay.
• Disclosure encompasses any such compounds disclosed herewith, e.g., a Compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI and/or Formula VII.
• treatment and “treating” are to be understood accordingly as embracing prophylaxis and treatment or amelioration of symptoms of disease as well as treatment of the cause of the disease.
• the word “effective amount” is intended to encompass a therapeutically effective amount to treat a specific disease or disorder.
• patient or “subject” includes human or non-human (i.e., animal) patient.
• the disclosure encompasses both human and nonhuman.
• the disclosure encompasses nonhuman.
• the term encompasses human.
• Dosages employed in practicing the present disclosure will of course vary depending, e.g. on the particular disease or condition to be treated, the particular Compound of the Disclosure used, the mode of administration, and the therapy desired.
• Compounds of the Disclosure may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally.
• satisfactory results, e.g. for the treatment of diseases as hereinbefore set forth are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg.
• an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 150 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form.
• Unit dosage forms for oral administration thus for example may comprise from about 0.2 to 75 or 150 mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a Compound of the Disclosure, together with a pharmaceutically acceptable diluent or carrier therefor.
• compositions comprising Compounds of the Disclosure may be prepared using conventional diluents or excipients and techniques known in the galenic art.
• oral dosage forms may include tablets, capsules, solutions, suspensions and the like.
• Example 1 Measurement of PDEIB inhibition in vitro using IMAP Phosphodiesterase Assay Kit
• Phosphodiesterase I B is a calcium/calmodulin dependent phosphodiesterase enzyme that converts cyclic guanosine monophosphate (cGMP) to 5'- guanosine monophosphate (5'-GMP). PDEIB can also convert a modified cGMP substrate, such as the fluorescent molecule cGMP -fluorescein, to the corresponding GMP-fluorescein. The generation of GMP-fluorescein from cGMP-fluorescein can be quantitated, using, for example, the IMAP (Molecular Devices, Sunnyvale, CA) immobilized-metal affinity particle reagent.
• IMAP Molecular Devices, Sunnyvale, CA
• the IMAP reagent binds with high affinity to the free 5'- phosphate that is found in GMP-fluorescein and not in cGMP-fluorescein.
• the resulting GMP-fluorescein — IMAP complex is large relative to cGMP-fluorescein.
• Small fluorophores that are bound up in a large, slowly tumbling, complex can be distinguished from unbound fluorophores, because the photons emitted as they fluoresce retain the same polarity as the photons used to excite the fluorescence.
• cGMP -fluorescein which cannot be bound to
• Assay The following phosphodiesterase enzymes may be used: 3',5'-cyclic- nucleotide-specific bovine brain phosphodiesterase (Sigma, St. Louis, MO) (predominantly PDEIB) and recombinant full length human PDE1 A and PDE1B (r- hPDEl A and r-hPDElB respectively) which may be produced e.g., in HEK or SF9 cells by one skilled in the art.
• the PDE1 enzyme is reconstituted with 50% glycerol to 2.5 U/ml. One unit of enzyme will hydrolyze 1.0 pm of 3',5'-cAMP to 5'-AMP per min at pH 7.5 at 30°C.
• reaction buffer (30 pM CaCl 2 , 10 U/ml of calmodulin (Sigma P2277), lOmM Tris-HCl pH 7.2, lOmM MgCl 2 , 0.1% BSA, 0.05% NaN3 ) to yield a final concentration of 1.25mU/ml.
• 99 pi of diluted enzyme solution is added into each well in a flat bottom 96-well polystyrene plate to which 1 pi of test compound dissolved in 100% DMSO is added. The compounds are mixed and pre-incubated with the enzyme for 10 min at room temperature.
• the FL-GMP conversion reaction is initiated by combining 4 parts enzyme and inhibitor mix with 1 part substrate solution (0.225 pM) in a 384-well microtiter plate. The reaction is incubated in dark at room temperature for 15 min. The reaction is halted by addition of 60 pL of binding reagent (1:400 dilution of IMAP beads in binding buffer supplemented with 1 : 1800 dilution of antifoam) to each well of the 384-well plate. The plate is incubated at room temperature for 1 hour to allow IMAP binding to proceed to completion, and then placed in an Envision multimode microplate reader (PerkinElmer, Shelton, CT) to measure the fluorescence polarization (Amp).
• Envision multimode microplate reader PerkinElmer, Shelton, CT
• IC50 values are determined by measuring enzyme activity in the presence of 8 to 16 concentrations of compound ranging from 0.0037 nM to 80,000 nM and then plotting drug concentration versus AmP, which allows IC50 values to be estimated using nonlinear regression software (XLFit; IDBS, Cambridge, MA).
• Compound 1 is identified as a specific PDE1 inhibitor of formula:
• This compound has efficacy at sub-nanomolar levels vs PDE1 (ICso of 0.058nM for bovine brain PDE1 in the assay described above) and high selectivity over other PDE families, as depicted on the following table:
• the compound is also highly selective versus a panel of 63 receptors, enzymes, and ion channels. These data, and data for other PDE1 inhibitors described herein, are described in Li et al., J. Med. Chem. 2016: 59, 1149-1164, the contents of which are incorporated herein by reference.
• PDE1 inhibitor in guinea pig cardiomyocytes Myocytes were isolated according to Liu et al., Circulation Research, 2014. A thoracotomy was performed on anesthetized guinea pigs to remove the heart. The aorta was cannulated on a Langendorf apparatus fitted with a heating jacket circulating water at 37 °C, and were retrogradely perfused for 5 minutes at 8 ml/min. The perfusate was switched to a Tyrode’s solution containing collagen type 2 (Worthington) and protease type 14 (Sigma-Aldrich) for 7-9 minutes.
• Tyrode s solution containing collagen type 2 (Worthington) and protease type 14 (Sigma-Aldrich) for 7-9 minutes.

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