WO2010002492A1 - Procédés d’utilisation de dérivés d’adénine pour le traitement du diabète et d’autres troubles - Google Patents

Procédés d’utilisation de dérivés d’adénine pour le traitement du diabète et d’autres troubles Download PDF

Info

Publication number
WO2010002492A1
WO2010002492A1 PCT/US2009/042095 US2009042095W WO2010002492A1 WO 2010002492 A1 WO2010002492 A1 WO 2010002492A1 US 2009042095 W US2009042095 W US 2009042095W WO 2010002492 A1 WO2010002492 A1 WO 2010002492A1
Authority
WO
WIPO (PCT)
Prior art keywords
heteroatom
drug
subject
substituted
pancreatic
Prior art date
Application number
PCT/US2009/042095
Other languages
English (en)
Inventor
Christopher Rhodes
Cristina Alarcon
Original Assignee
University Of Chicago
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Chicago filed Critical University Of Chicago
Publication of WO2010002492A1 publication Critical patent/WO2010002492A1/fr

Links

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
    • A61K31/52—Purines, e.g. adenine

Definitions

  • the present invention relates generally to the treatment and prevention of diabetes.
  • the methods and compositions of this invention comprise the use of small molecules.
  • Type 1 diabetes is known to be caused by the selective autoimmune destruction of pancreatic ⁇ -cells that leads to a severe state of insulin insufficiency requiring insulin injection therapy and close to constant monitoring to avoid complications setting in.
  • insulin therapy is not a cure for diabetes, which would require the replenishment of a functional ⁇ -cell mass.
  • One very active area of type 1 diabetes research is to search for a pharmacological means to promote ⁇ -cell growth, regeneration and/or survival.
  • T2DM type 2 diabetes mellitus
  • Pancreatic ⁇ -cell mass is flexible and can adjust to compensate for a rise in metabolic load (as in pregnancy or obesity) (Rhodes, 2005; Sorenson and Brelje, 1997), in recovery from pancreatic injury (Smith et ah, 1991), or after surgical removal of an insulinoma (Chick et ah, 1977). Conversely, it can decrease postpartum (Scaglia et ah, 1995), or with controlled weight loss in treatment of obesity (Ferrannini et ah, 2004). Signal transduction mechanisms that control pancreatic ⁇ -cell growth, regeneration and survival at the molecular level have fundamental relevance for type 1 diabetes.
  • Changes in net ⁇ -cell growth are set by the balance between the sum of ⁇ -cell hypertrophy ( ⁇ -cell size) and hyperplasia ( ⁇ -cell replication and neogenesis), minus the incidence of ⁇ -cell death (either via apoptosis (Butler et al., 2003), necrosis (Olejnicka et al, 1999) and/or autophagic mediated cell death (Marsh et al, 2007; Rhodes, 2005)).
  • Many peptide growth factors, certain nutrients, peptide hormones and neural connections have been implicated in regulating ⁇ -cell growth (Lingohr et al, 2002). However, few of these have been shown to have physiological relevance.
  • Sulphonylureas these target the ATP-sensitive K- channel to trigger insulin secretion.
  • Use of sulphonylureas is problematic since their actions are not glucose dependent, which can cause unwanted and potentially dangerous hypoglycemic episodes for the patient.
  • sulphonylureas do not upregulate insulin production (to replenish secreted insulin) and the secretory capacity of the ⁇ -cell is reduced leading to ⁇ -cell exhaustion. This can result in acceleration of the patient towards insulin injection therapy. As a consequence the clinical use of sulphonylureas is in fast decline.
  • GLP-I analogues (ByettaTM): this is a stable form of the endogenous Glucagon-Like Peptide (GLP)-I incretin peptide that potentiates insulin secretion (via a specific G-protein coupled receptor and elevation of [CAMP] 1 ) in a glucose dependent manner.
  • the glucose dependency means that far fewer instances of hypoglycemia are caused by GLP-I analogs in comparison to sulphonylureas.
  • GLP-I analogs may also have beneficial effects on promoting ⁇ -cell growth and survival.
  • GLP-I can lead to a beneficial gradual weight loss in obese type 2 diabetics.
  • DPP-IV inhibitors This is a new class of drugs that delays the degradation of endogenous GLP-I and has modest effects on potentiating glucose-induced insulin secretion. DPP-IV inhibitors appear safe, have relatively few side effects and can be administered orally. However, the effects of DPP-IV inhibitors effects are quite weak and they need to be combined with other type 2 diabetes drugs such as Metformin or TZDs.
  • this invention provides methods of treating and preventing diabetes and other diseases using small molecules.
  • the present invention provide methods of treating and/or preventing glucose-associated disorders, such as diabetes and insulin secretory dysfunction. Also provided are methods of stimulating and/or producing pancreatic ⁇ -cells. Also provided are methods of prolonging the honey-moon period in the pathogenesis of type 1 diabetes in a subject. These methods all comprise administering an effective amount of an adenine derivative to a subject and/or contacting a pancreatic ⁇ -cell with an adenine derivative.
  • the diabetes is type 1, in others it is type 2.
  • the glucose-dependent stimulation of insulin and/or proinsulin secretion, biosynthesis and/or processing is potentiated in the subject.
  • the regeneration, growth, survival and/or neogenesis of pancreatic ⁇ -cells in the subject is promoted.
  • the promotion occurs through the induction of anti-apoptotic regulatory gene expression in these cells.
  • the anti-apoptotic regulatory gene can be IRS-2 or CREB.
  • the subject in which the glucose-associated disorder is to be treated or prevented can be a primate, such as a human.
  • the method can further comprise identifying a subject in need of treatment or prevention. Examples of identifying subjects includes those having a family or patient history of diabetes, or those having symptoms of diabetes.
  • the method further comprises testing the subject for symptoms of diabetes and/or monitoring the level of sugar in the subject's blood.
  • the method of simulating and/or producing pancreatic ⁇ -cells takes place ex vivo. In some variations, the method includes culturing the pancreatic ⁇ -cells.
  • pancreatic ⁇ -cell can be cultured with a growth factor ⁇ e.g., TGF- ⁇ l,
  • pancreatic ⁇ -cell is purified after being stimulated, produced and/or cultured.
  • the pancreatic ⁇ -cell is stimulated to (1) secrete insulin, (2) potentiate the increase in insulin production in response to glucose, (3) increase the expression of pro-survival genes, and/or (4) increase the level of cAMP in the pancreatic ⁇ - cell.
  • the pancreatic ⁇ -cell is of human, bovine, equine, canine, feline, murine, rat or chick origin.
  • adenine derivatives are defined as compounds of the formula:
  • R 1 and R 2 are independently attached to either carbon or nitrogen atoms of either ring shown above; further wherein R 1 and R 2 are independently hydrogen, hydroxy, amino, cyano, halo, nitro, mercapto, or a heteroatom-substituted or heteroatom-unsubstituted alkyl( cl- c8), alkenyl( cl-C 8), alkynyl( cl- c8), aryl( cl-C 8), aralkyl( C2-C 8), acyl( cl- c8), alkoxyfci-cs), alkenyloxyfci-cs), alkynyloxyfci-cs), aryloxyfci-cs), aralkyloxy( C2- c8), acyloxy( cl- c8), alkylamino( cl- c8), alkenylamino( cl- c8), alkenyla
  • the invention specifically contemplates that a subgenus of the above formula may be excluded.
  • R 2 is hydrogen and/or R 1 is heteroatom-substituted or heteroatom-unsubstituted alkyl(ci-c4), such as a heteroatom-unsubstituted alkyl(ci-c3).
  • the adenine derivative is one of the following:
  • the adenine derivative is soluble in either water or bodily fluids.
  • the adenine derivative can be administered systemically.
  • it can be administered intravenously, intra-arterially, intra-muscularly, intra- peritoneally, subcutaneously or orally.
  • the effective amount is less than or equal to 500 mg daily.
  • the effective amount is from about 1 mg/kg of body weight to about 15 mg/kg of body weight, for example about 7 mg/kg of body weight.
  • the adenine derivative can be administered by contacting a pancreatic ⁇ -cell during ex vivo purging.
  • the invention provides in some embodiments that the effective amount of adenine derivative is administered as a single dose per day, at two of more doses per day.
  • the effective amount may also be calculated based on the level of sugar in the subject's blood.
  • the methods of the invention further comprise administering immunosuppressive therapy, wherein the adenine derivative and the immunosuppressive therapy are provided to the subject in an effective amount to treat or prevent diabetes in the subject.
  • the immunosuppressive therapy comprises administering an anti- CD3 monoclonal antibody to the subject.
  • the invention provides methods comprising administering to the subject a second drug, wherein the adenine derivative and the second drug are provided in an effective amount to treat diabetes in the subject.
  • second drugs examples include dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin, vildagliptin, SYR-322, BMS 477118 and GSK 823093), biguanides ⁇ e.g., metformin), thiazolidinedione (TZD) or thiazolidinedione derivatives (e.g., pioglitazone, rosiglitazone and troglitazone), sulfonylurea derivative (e.g., tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride and gliclazide), meglitinide (e.g., repaglinide, mitiglinide and nateglinide), insulin, alpha-glucosidase inhibitors (e.g., acarbose, miglitol and voglibose
  • the method further comprises administering to the subject a second drug and a third drug, wherein the adenine derivative, the second drug and the third drug are provided in an effective amount to treat diabetes in the subject.
  • the second and third drugs can be independently selected from the group recited above.
  • a non- limiting example of a possible combination includes using an adenine derivative with a DPP- 4 inhibitor and a biguanide, such as metformin.
  • Another non-limiting example includes using an adenine derivative with an amylin analog and a leptin analog.
  • FIGS. IA & B The glucose-dependent potentiation of insulin secretion by certain methylated adenine analogs.
  • FIG. IA shows a preliminary study in isolated rat islets (mean ⁇ SE of > 3 experiments), where 250 ⁇ M 3-MA, M-methyl adenine (M)-MA) or 9-methyl adenine (9-MA) significantly potentiated glucose-induced insulin secretion.
  • 250 ⁇ M 1-methyl adenine (1-MA), 7-methyl adenine (7-MA), adenosine, adenine, cytosine, guanine or thymine had no effect on glucose-induced insulin secretion.
  • As only some methylated forms of adenine i.e.
  • FIG. IB shows the glucose-dependence of 250 ⁇ M 3-MA, M-MA or 9-MA on potentiating insulin secretion that is equivalent, if not better, than the effect of the GLP-I analog exendin-4 (5nM).
  • FIG. 2. The effect of 3-MA (30 ⁇ g/g oral dose) in an IPGTT in normal adult rats.
  • FIG. 3 M)-MA and 9-MA potentiate glucose-induced rat islet ⁇ -cell replication. In both INS-I cells and isolated rat islets, M)-MA and 9-MA (250 ⁇ M) significantly potentiate ⁇ - cell proliferation at glucose concentrations >8mM when assessed by [ 3 H]thymidine incorporation over a 48h period. This figure shows such an effect at a stimulatory HmM glucose (data are a mean ⁇ SE (n > 3)).
  • FIG. 4. 3-MA, M-MA and 9-MA protect rat islet ⁇ -cells against cvtokine-induced apoptosis.
  • Isolated rat islets were exposed to a cytokine cocktail of interleukin-l ⁇ (IL- l ⁇ , 10ng/ml), tumor necrosis factor- ⁇ (TNF- ⁇ , 50ng/ml) and interferon- ⁇ (IFN- ⁇ , 50ng/ml), at a basal 3mM glucose in the presence or absence of 3MA, M-MA or 9-MA (250 ⁇ M) for 24h.
  • IL- l ⁇ interleukin-l ⁇
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IFN- ⁇ interferon- ⁇
  • FIG. 5 3-MA, M-MA and 9-MA increase IRS-2 expression and decrease pro- apoptotic gene expression in isolated rat islets.
  • This figure shows that 250 ⁇ M 3-MA, M-MA, and 9-MA, each augment a 15mM glucose-induced IRS-2 protein expression in isolated rat islets within 6h.
  • the 3MA/M-MA/9-MA augmented increase in IRS-2 expression in rat islet ⁇ -cells is associated with decreased expression of the pro-apoptotic genes, Bax, Bad and Bak, but not the anti-apoptotic genes Bcl-2 or BCI-X L , which are unchanged relative to a loading control protein, the 85kD subunit of PI3K.
  • 3-MA increases glucose-induced insulin secretion and improve glucose tolerance in normal rats.
  • Normal Sprague-Dawley rats, -200 g body weight (bw) were fasted overnight, then subjected to an intraperitoneal glucose tolerance test (IPGTT), using a lmg glucose/g bw dose of glucose.
  • IPGTTs were conducted with 3-MA (30 ⁇ g/g bw) or vehicle control, given IP, 15 minutes prior to the glucose dose.
  • Tail blood samples were collected at the indicated time pints and glucose (FIG. 6A) and insulin levels (FIG. 6B) were subsequently measured.
  • the present invention relates generally to the prevention and treatment of glucose-associated diseases such as diabetes using adenine derivatives having the formula:
  • IC 50 refers to an inhibitory dose which results in 50% of the maximum response obtained.
  • the term “inhibiting,” “reducing,” or “prevention,” or any variation of these terms, when used in the claims and/or the specification includes any measurable decrease or complete inhibition to achieve a desired result.
  • the use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.”
  • the term “patient” or “subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dogs, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate.
  • Non-limiting examples of human subjects are adults, juveniles, infants and fetuses.
  • "predominantly one enantiomer” means that the compound contains at least 85% of one enantiomer, or more preferably at least 90% of one enantiomer, or even more preferably at least 95% of one enantiomer, or most preferably at least 99% of one enantiomer.
  • the phrase "substantially free from other optical isomers” means that the composition contains at most 5% of another enantiomer or diastereomer, more preferably 2% of another enantiomer or diastereomer, and most preferably 1% of another enantiomer or diastereomer.
  • water soluble means that the compound dissolves in water at least to the extent of 0.010 mole/liter or is classified as soluble according to literature precedence.
  • amino means -NH 2 ; the term “nitro” means -NO 2 ; the term “halo” designates -F, -Cl, -Br or -I; the term “mercapto” means -SH; the term “cyano” means -CN; the term “azido” means -N 3 ; the term “silyl” means -SiH 3 , and the term “hydroxy” means -OH.
  • alkyl includes straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic), cyclic alkyl, heteroatom-unsubstituted alkyl, heteroatom-substituted alkyl, heteroatom-unsubstituted alkyl(c n ), and heteroatom-substituted alkyl(c n )-
  • heteroatom-unsubstituted alkyl(c n ) refers to a radical, having a linear or branched, cyclic or acyclic structure, further having no carbon-carbon double or triple bonds, further having a total of n carbon atoms, all of which are nonaromatic, 3 or more hydrogen atoms, and no heteroatoms.
  • a heteroatom-unsubstituted alkyl(ci-cio) has 1 to 10 carbon atoms.
  • heteroatom-substituted alkyl(c n ) refers to a radical, having a single saturated carbon atom as the point of attachment, no carbon-carbon double or triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, all of which are nonaromatic, 0, 1 , or more than one hydrogen atom, at least one heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted alkyl(ci-cio) has 1 to 10 carbon atoms.
  • the following groups are all non- limiting examples of heteroatom- substituted alkyl groups: trifluoromethyl, -CH 2 F, -CH 2 Cl, -CH 2 Br, -CH 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CF 3 , -CH 2 OC(O)CH 3 , -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 Cl, -CH 2 CH 2 OH, CH 2 CH 2 OC(O)CH 3 , -CH 2 CH 2 NHCO 2 C(CH 3 ) 3 , and -CH 2 Si(CH 3 ) 3 .
  • alkanediyl includes straight-chain alkanediyl, branched-chain alkanediyl, cycloalkanediyl, cyclic alkanediyl, heteroatom-unsubstituted alkanediyl, heteroatom- substituted alkanediyl, heteroatom-unsubstituted alkanediyl(cn), and heteroatom-substituted alkanediyl(cn)-
  • heteroatom-unsubstituted alkanediyl (c n ) refers to a diradical, having a linear or branched, cyclic or acyclic structure, further having no carbon-carbon double or triple bonds, further having a total of n carbon atoms, all of which are nonaromatic, 2 or more hydrogen atoms, and no heteroatoms.
  • a heteroatom-unsubstituted alkanediyl(ci-cio) has 1 to 10 carbon atoms.
  • the groups, -CH 2 - (methylene), -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -, are all non-limiting examples of heteroatom-unsubstituted alkanediyl groups.
  • heteroatom-substituted alkanediyl(cn) refers to a radical, having two points of attachment to one or two saturated carbon atoms, no carbon-carbon double or triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, all of which are nonaromatic, O, 1, or more than one hydrogen atom, at least one heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted alkanediyl(ci-cio) has 1 to 10 carbon atoms.
  • the following groups are all non-limiting examples of heteroatom- substituted alkanediyl groups: -CH(F)-, -CF 2 -, -CH(Cl)-, -CH(OH)-, -CH(OCH 3 )-, and -CH 2 CH(Cl)-.
  • alkenyl includes straight-chain alkenyl, branched-chain alkenyl, cycloalkenyl, cyclic alkenyl, heteroatom-unsubstituted alkenyl, heteroatom-substituted alkenyl, heteroatom-unsubstituted alkenyl(c n ), and heteroatom-substituted alkenyl(cn)-
  • heteroatom-unsubstituted alkenyl(c n ) refers to a radical, having a linear or branched, cyclic or acyclic structure, further having at least one nonaromatic carbon-carbon double bond, but no carbon-carbon triple bonds, a total of n carbon atoms, three or more hydrogen atoms, and no heteroatoms.
  • a heteroatom-unsubstituted alkenyl(c 2- cio) has 2 to 10 carbon atoms.
  • heteroatom-substituted alkenyl(c n ) refers to a radical, having a single nonaromatic carbon atom as the point of attachment and at least one nonaromatic carbon-carbon double bond, but no carbon-carbon triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, and at least one heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted alkenyl(c2-cio) has 2 to 10 carbon atoms.
  • alkynyl includes straight-chain alkynyl, branched-chain alkynyl, cycloalkynyl, cyclic alkynyl, heteroatom-unsubstituted alkynyl, heteroatom-substituted alkynyl, heteroatom-unsubstituted alkynyl(cn), and heteroatom-substituted alkynyl(cn)-
  • heteroatom-unsubstituted alkynyl(cn) refers to a radical, having a linear or branched, cyclic or acyclic structure, further having at least one carbon-carbon triple bond, a total of n carbon atoms, at least one hydrogen atom, and no heteroatoms.
  • a heteroatom- unsubstituted alkynyl(c2-cio) has 2 to 10 carbon atoms.
  • heteroatom-substituted alkynyl(cn) refers to a radical, having a single nonaromatic carbon atom as the point of attachment and at least one carbon-carbon triple bond, further having a linear or branched, cyclic or acyclic structure, and having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, and at least one heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted alkynyl(c2-cio) has 2 to 10 carbon atoms.
  • aryl includes heteroatom-unsubstituted aryl, heteroatom-substituted aryl, heteroatom-unsubstituted aryl( Cn ), heteroatom-substituted aryl( Cn ), heteroaryl, heterocyclic aryl groups, carbocyclic aryl groups, biaryl groups, and single-valent radicals derived from polycyclic fused hydrocarbons (PAHs).
  • PAHs polycyclic fused hydrocarbons
  • heteroatom-unsubstituted aryl(cn) refers to a radical, having a single carbon atom as a point of attachment, wherein the carbon atom is part of an aromatic ring structure containing only carbon atoms, further having a total of n carbon atoms, 5 or more hydrogen atoms, and no heteroatoms.
  • a heteroatom- unsubstituted aryl(c6-cio) has 6 to 10 carbon atoms.
  • heteroatom- unsubstituted aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C 6 H 4 CH 2 CH 3 , -C 6 H 4 CH 2 CH 2 CH 3 , -C 6 H 4 CH(CH 3 ) 2 , -C 6 H 4 CH(CH 2 ) 2 ,
  • heteroatom-substituted aryl(c n ) refers to a radical, having either a single aromatic carbon atom or a single aromatic heteroatom as the point of attachment, further having a total of n carbon atoms, at least one hydrogen atom, and at least one heteroatom, further wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-unsubstituted heteroaryl(ci-cio) has 1 to 10 carbon atoms.
  • Non- limiting examples of heteroatom-substituted aryl groups include the groups: -C 6 H 4 F, -C 6 H 4 Cl, -C 6 H 4 Br, -C 6 H 4 I, -C 6 H 4 OH, -C 6 H 4 OCH 3 , -C 6 H 4 OCH 2 CH 3 , -C 6 H 4 OC(O)CH 3 , -C 6 H 4 NH 2 , -C 6 H 4 NHCH 3 , -C 6 H 4 N(CH 3 ) 2 , -C 6 H 4 CH 2 OH, -C 6 H 4 CH 2 OC(O)CH 3 , -C 6 H 4 CH 2 NH 2 , -C 6 H 4 CF 3 , -C 6 H 4 CN, -C 6 H 4 CHO, -C 6 H 4 CHO, -C 6 H 4 C(O)CH 3 , -C 6 H 4 C(O)C 6 H 5 , -C 6 H
  • aralkyl includes heteroatom-unsubstituted aralkyl, heteroatom-substituted aralkyl, heteroatom-unsubstituted aralkyl(c n ), heteroatom-substituted aralkyl(c n ), heteroaralkyl, and heterocyclic aralkyl groups.
  • heteroatom-unsubstituted aralkyl(cn) refers to a radical, having a single saturated carbon atom as the point of attachment, further having a total of n carbon atoms, wherein at least 6 of the carbon atoms form an aromatic ring structure containing only carbon atoms, 7 or more hydrogen atoms, and no heteroatoms.
  • a heteroatom-unsubstituted aralkyl(c7-cio) has 7 to 10 carbon atoms.
  • Non-limiting examples of heteroatom-unsubstituted aralkyls are: phenylmethyl (benzyl, Bn) and phenylethyl.
  • heteroatom-substituted aralkyl(c n ) refers to a radical, having a single saturated carbon atom as the point of attachment, further having a total of n carbon atoms, O, 1, or more than one hydrogen atom, and at least one heteroatom, wherein at least one of the carbon atoms is incorporated an aromatic ring structures, further wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted heteroaralkyl(c 2- cio) has 2 to 10 carbon atoms.
  • acyl includes straight-chain acyl, branched-chain acyl, cycloacyl, cyclic acyl, heteroatom-unsubstituted acyl, heteroatom-substituted acyl, heteroatom-unsubstituted acyl(cn), heteroatom-substituted acyl(cn), alkylcarbonyl, alkoxycarbonyl and aminocarbonyl groups.
  • heteroatom-unsubstituted acyl(cn) refers to a radical, having a single carbon atom of a carbonyl group as the point of attachment, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 1 or more hydrogen atoms, a total of one oxygen atom, and no additional heteroatoms.
  • a heteroatom-unsubstituted acyl(ci-cio) has 1 to 10 carbon atoms.
  • the groups, -CHO, -C(O)CH 3 , -C(O)CH 2 CH 3 , -C(O)CH 2 CH 2 CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)CH(CH 2 ) 2 , -C(O)C 6 H 5 , -C(O)C 6 H 4 CH 3 , -C(O)C 6 H 4 CH 2 CH 3 , and -COC 6 H 3 (CH 3 ) 2 are non-limiting examples of heteroatom-unsubstituted acyl groups.
  • heteroatom-substituted acyl(c n ) refers to a radical, having a single carbon atom as the point of attachment, the carbon atom being part of a carbonyl group, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, O, 1, or more than one hydrogen atom, at least one additional heteroatom, in addition to the oxygen of the carbonyl group, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted acyl(ci-cio) has 1 to 10 carbon atoms..
  • the groups, -C(O)CH 2 CF 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 CH 2 CH 2 CH 3 , -CO 2 CH(CH 3 ) 2 , -CO 2 CH(CH 2 ) 2 , -C(O)NH 2 (carbamoyl), -C(O)NHCH 3 , -C(O)NHCH 2 CH 3 , -CONHCH(CH 3 ) 2 , -CONHCH(CH 2 ) 2 , -CON(CH 3 ) 2 , and -CONHCH 2 CF 3 , are non-limiting examples of heteroatom-substituted acyl groups.
  • alkoxy includes straight-chain alkoxy, branched-chain alkoxy, cycloalkoxy, cyclic alkoxy, heteroatom-unsubstituted alkoxy, heteroatom-substituted alkoxy, heteroatom-unsubstituted alkoxy(c n ), and heteroatom-substituted alkoxy(c n )-
  • heteroatom-unsubstituted alkoxy(cn) refers to a group, having the structure -OR, in which R is a heteroatom-unsubstituted alkyl(c n ), as that term is defined above.
  • Heteroatom- unsubstituted alkoxy groups include: -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , and -OCH(CH 2 ) 2 .
  • the term "heteroatom-substituted alkoxy(cn)" refers to a group, having the structure -OR, in which R is a heteroatom-substituted alkyl(c n ), as that term is defined above.
  • -OCH 2 CF 3 is a heteroatom-substituted alkoxy group.
  • alkenyloxy includes straight-chain alkenyloxy, branched-chain alkenyloxy, cycloalkenyloxy, cyclic alkenyloxy, heteroatom-unsubstituted alkenyloxy, heteroatom-substituted alkenyloxy, heteroatom-unsubstituted alkenyloxy(cn), and heteroatom- substituted alkenyloxy(cn)-
  • heteroatom-unsubstituted alkenyloxy(c n ) refers to a group, having the structure -OR, in which R is a heteroatom-unsubstituted alkenyl(c n ), as that term is defined above.
  • heteroatom-substituted alkenyloxy(cn) refers to a group, having the structure -OR, in which R is a heteroatom-substituted alkenyl(c n ), as that term is defined above.
  • alkynyloxy includes straight-chain alkynyloxy, branched-chain alkynyloxy, cycloalkynyloxy, cyclic alkynyloxy, heteroatom-unsubstituted alkynyloxy, heteroatom-substituted alkynyloxy, heteroatom-unsubstituted alkynyloxy(cn), and heteroatom-substituted alkynyloxy(cn)-
  • heteroatom-unsubstituted alkynyloxy(cn) refers to a group, having the structure -OR, in which R is a heteroatom-unsubstituted alkynyl(cn), as that term is defined above.
  • heteroatom-substituted alkynyloxy(cn) refers to a group, having the structure -OR, in which R is a heteroatom-substituted alkynyl(cn), as that term is defined above.
  • aryloxy includes heteroatom-unsubstituted aryloxy, heteroatom- substituted aryloxy, heteroatom-unsubstituted aryloxy(cn), heteroatom-substituted aryloxy(cn), heteroaryloxy, and heterocyclic aryloxy groups.
  • heteroatom- unsubstituted aryloxy(cn) refers to a group, having the structure -OAr, in which Ar is a heteroatom-unsubstituted aryl(c n ), as that term is defined above.
  • a non-limiting example of a heteroatom-unsubstituted aryloxy group is -OC O H S .
  • heteroatom-substituted aryloxy(cn) refers to a group, having the structure -OAr, in which Ar is a heteroatom- substituted aryl(cn), as that term is defined above.
  • aralkyloxy includes heteroatom-unsubstituted aralkyloxy, heteroatom- substituted aralkyloxy, heteroatom-unsubstituted aralkyloxy(cn), heteroatom-substituted aralkyloxy(cn), heteroaralkyloxy, and heterocyclic aralkyloxy groups.
  • heteroatom- unsubstituted aralkyloxy(cn) refers to a group, having the structure -OAr, in which Ar is a heteroatom-unsubstituted aralkyl(c n ), as that term is defined above.
  • heteroatom- substituted aralkyloxy(cn) refers to a group, having the structure -OAr, in which Ar is a heteroatom-substituted aralkyl(c n ), as that term is defined above.
  • acyloxy includes straight-chain acyloxy, branched-chain acyloxy, cycloacyloxy, cyclic acyloxy, heteroatom-unsubstituted acyloxy, heteroatom-substituted acyloxy, heteroatom-unsubstituted acyloxy(c n ), heteroatom-substituted acyloxy(c n ), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, and carboxylate groups.
  • heteroatom-unsubstituted acyloxy(cn) refers to a group, having the structure -OAc, in which Ac is a heteroatom-unsubstituted acyl(cn), as that term is defined above.
  • -OC(O)CH 3 is a non-limiting example of a heteroatom-unsubstituted acyloxy group.
  • heteroatom-substituted acyloxy(c n ) refers to a group, having the structure -OAc, in which Ac is a heteroatom-substituted acyl(cn), as that term is defined above.
  • -OC(O)OCH 3 and -OC(O)NHCH 3 are non-limiting examples of heteroatom-unsubstituted acyloxy groups.
  • alkylamino includes straight-chain alkylamino, branched-chain alkylamino, cycloalkylamino, cyclic alkylamino, heteroatom-unsubstituted alkylamino, heteroatom-substituted alkylamino, heteroatom-unsubstituted alkylamino(cn), and heteroatom-substituted alkylamino(cn)-
  • heteroatom-unsubstituted alkylamino(cn) refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two saturated carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, containing a total of n carbon atoms, all of which are nonaromatic, 4 or more hydrogen atoms, a total of 1 nitrogen atom, and no additional heteroatoms.
  • heteroatom-unsubstituted alkylamino(ci-cio) has 1 to 10 carbon atoms.
  • heteroatom-unsubstituted alkylamino(cn) includes groups, having the structure -NHR, in which R is a heteroatom-unsubstituted alkyl(c n ), as that term is defined above.
  • a heteroatom-unsubstituted alkylamino group would include -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , -NHCH(CH 2 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 2 CH 3 , -NHCH 2 CH(CH 3 ) 2 , -NHC(CH 3 ) 3 , -N(CH 3 ) 2 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 ) 2 , 7V-pyrrolidinyl, and TV-piperidinyl.
  • heteroatom-substituted alkylamino(cn) refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two saturated carbon atoms attached to the nitrogen atom, no carbon- carbon double or triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, all of which are nonaromatic, 0, 1, or more than one hydrogen atom, and at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • heteroatom- substituted alkylamino(ci-cio) has 1 to 10 carbon atoms.
  • heteroatom-substituted alkylamino(cn) includes groups, having the structure -NHR, in which R is a heteroatom- substituted alkyl(cn), as that term is defined above.
  • alkenylamino includes straight-chain alkenylamino, branched-chain alkenylamino, cycloalkenylamino, cyclic alkenylamino, heteroatom-unsubstituted alkenylamino, heteroatom-substituted alkenylamino, heteroatom-unsubstituted alkenylamino(cn), heteroatom-substituted alkenylamino(cn), dialkenylamino, and alkyl(alkenyl)amino groups.
  • heteroatom-unsubstituted alkenylamino(cn) refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, containing at least one nonaromatic carbon-carbon double bond, a total of n carbon atoms, 4 or more hydrogen atoms, a total of one nitrogen atom, and no additional heteroatoms.
  • a heteroatom-unsubstituted alkenylamino(c 2- cio) has 2 to 10 carbon atoms.
  • heteroatom-unsubstituted alkenylamino(cn) includes groups, having the structure -NHR, in which R is a heteroatom-unsubstituted alkenyl(c n ), as that term is defined above.
  • heteroatom-substituted alkenylamino(cn) refers to a radical, having a single nitrogen atom as the point of attachment and at least one nonaromatic carbon- carbon double bond, but no carbon-carbon triple bonds, further having one or two carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, and at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • heteroatom-substituted alkenylamino(c2-cio) has 2 to 10 carbon atoms.
  • heteroatom-substituted alkenylamino(cn) includes groups, having the structure -NHR, in which R is a heteroatom- substituted alkenyl(cn), as that term is defined above.
  • alkynylamino includes straight-chain alkynylamino, branched-chain alkynylamino, cycloalkynylamino, cyclic alkynylamino, heteroatom-unsubstituted alkynylamino, heteroatom-substituted alkynylamino, heteroatom-unsubstituted alkynylamino(cn), heteroatom-substituted alkynylamino(cn), dialkynylamino, alkyl(alkynyl)amino, and alkenyl(alkynyl)amino groups.
  • heteroatom-unsubstituted alkynylamino(cn) refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, containing at least one carbon-carbon triple bond, a total of n carbon atoms, at least one hydrogen atoms, a total of one nitrogen atom, and no additional heteroatoms.
  • a heteroatom-unsubstituted alkynylamino(c2-cio) has 2 to 10 carbon atoms.
  • heteroatom-unsubstituted alkynylamino(cn) includes groups, having the structure -NHR, in which R is a heteroatom- unsubstituted alkynyl(cn), as that term is defined above.
  • heteroatom-substituted alkynylamino(cn) refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two carbon atoms attached to the nitrogen atom, further having at least one nonaromatic carbon-carbon triple bond, further having a linear or branched, cyclic or acyclic structure, and further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, and at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • heteroatom-substituted alkynylamino(c2-cio) has 2 to 10 carbon atoms.
  • heteroatom-substituted alkynylamino(cn) includes groups, having the structure -NHR, in which R is a heteroatom-substituted alkynyl(cn), as that term is defined above.
  • arylamino includes heteroatom-unsubstituted arylamino, heteroatom- substituted arylamino, heteroatom-unsubstituted arylamino(cn), heteroatom-substituted arylamino(cn), heteroarylamino, heterocyclic arylamino, and alkyl(aryl)amino groups.
  • heteroatom-unsubstituted arylamino(cn) refers to a radical, having a single nitrogen atom as the point of attachment, further having at least one aromatic ring structure attached to the nitrogen atom, wherein the aromatic ring structure contains only carbon atoms, further having a total of n carbon atoms, 6 or more hydrogen atoms, a total of one nitrogen atom, and no additional heteroatoms.
  • a heteroatom-unsubstituted arylamino(c6-cio) has 6 to 10 carbon atoms.
  • heteroatom-unsubstituted arylamino(cn) includes groups, having the structure -NHR, in which R is a heteroatom-unsubstituted aryl(c n ), as that term is defined above.
  • heteroatom-substituted arylamino(cn) refers to a radical, having a single nitrogen atom as the point of attachment, further having a total of n carbon atoms, at least one hydrogen atom, at least one additional heteroatoms, that is, in addition to the nitrogen atom at the point of attachment, wherein at least one of the carbon atoms is incorporated into one or more aromatic ring structures, further wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • a heteroatom-substituted arylamino(c6-cio) has 6 to 10 carbon atoms.
  • heteroatom-substituted arylamino(cn) includes groups, having the structure -NHR, in which R is a heteroatom-substituted aryl(c n ), as that term is defined above.
  • aralkylamino includes heteroatom-unsubstituted aralkylamino, heteroatom-substituted aralkylamino, heteroatom-unsubstituted aralkylamino(cn), heteroatom- substituted aralkylamino(cn), heteroaralkylamino, heterocyclic aralkylamino groups, and diaralkylamino groups.
  • heteroatom-unsubstituted aralkylamino(cn) refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two saturated carbon atoms attached to the nitrogen atom, further having a total of n carbon atoms, wherein at least 6 of the carbon atoms form an aromatic ring structure containing only carbon atoms, 8 or more hydrogen atoms, a total of one nitrogen atom, and no additional heteroatoms.
  • a heteroatom-unsubstituted aralkylamino(c7-cio) has 7 to 10 carbon atoms.
  • heteroatom-unsubstituted aralkylamino(cn) includes groups, having the structure -NHR, in which R is a heteroatom-unsubstituted aralkyl(c n ), as that term is defined above.
  • heteroatom-substituted aralkylamino(cn) refers to a radical, having a single nitrogen atom as the point of attachment, further having at least one or two saturated carbon atoms attached to the nitrogen atom, further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein at least one of the carbon atom incorporated into an aromatic ring, further wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • heteroatom-substituted aralkylamino(c7-cio) has 7 to 10 carbon atoms.
  • heteroatom- substituted aralkylamino(cn) includes groups, having the structure -NHR, in which R is a heteroatom-substituted aralkyl(c n ), as that term is defined above.
  • amido includes straight-chain amido, branched-chain amido, cycloamido, cyclic amido, heteroatom-unsubstituted amido, heteroatom-substituted amido, heteroatom- unsubstituted amido(c n ), heteroatom-substituted amido(cn), alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, acylamino, alkylaminocarbonylamino, arylaminocarbonylamino, and ureido groups.
  • heteroatom-unsubstituted amido(cn) refers to a radical, having a single nitrogen atom as the point of attachment, further having a carbonyl group attached via its carbon atom to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 1 or more hydrogen atoms, a total of one oxygen atom, a total of one nitrogen atom, and no additional heteroatoms.
  • a heteroatom-unsubstituted amido(ci-cio) has 1 to 10 carbon atoms.
  • heteroatom-unsubstituted amido(cn) includes groups, having the structure -NHR, in which R is a heteroatom-unsubstituted acyl(c n ), as that term is defined above.
  • the group, -NHC(O)CH 3 is a non-limiting example of a heteroatom-unsubstituted amido group.
  • heteroatom-substituted amido(cn) refers to a radical, having a single nitrogen atom as the point of attachment, further having a carbonyl group attached via its carbon atom to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, further having a total of n aromatic or nonaromatic carbon atoms, 0, 1, or more than one hydrogen atom, at least one additional heteroatom in addition to the oxygen of the carbonyl group, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
  • heteroatom-substituted amido(ci-cio) has 1 to 10 carbon atoms.
  • heteroatom-substituted amido(c n ) includes groups, having the structure -NHR, in which R is a heteroatom-unsubstituted acyl(cn), as that term is defined above.
  • the group, -NHCO2CH3, is a non-limiting example of a heteroatom-substituted amido group.
  • a “chiral auxiliary” refers to a removable chiral group that is capable of influencing the stereoselectivity of a reaction. Persons of skill in the art are familiar with such compounds, and many are commercially available.
  • pharmaceutically acceptable salts refers to salts of compounds of this invention that are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of a compound of this invention with an inorganic or organic acid, or an organic base, depending on the substituents present on the compounds of the invention.
  • Non-limiting examples of inorganic acids which may be used to prepare pharmaceutically acceptable salts include: hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and the like.
  • organic acids which may be used to prepare pharmaceutically acceptable salts include: aliphatic mono- and dicarboxylic acids, such as oxalic acid, carbonic acid, citric acid, succinic acid, phenyl- heteroatom-substituted alkanoic acids, aliphatic and aromatic sulfuric acids and the like.
  • Pharmaceutically acceptable salts prepared from inorganic or organic acids thus include hydrochloride, hydrobromide, nitrate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydroiodide, hydro fluoride, acetate, propionate, formate, oxalate, citrate, lactate, p- toluenesulfonate, methanesulfonate, maleate, and the like.
  • Suitable pharmaceutically acceptable salts may also be formed by reacting the agents of the invention with an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like.
  • Pharmaceutically acceptable salts include the salts formed between carboxylate or sulfonate groups found on some of the compounds of this invention and inorganic cations, such as sodium, potassium, ammonium, or calcium, or such organic cations as isopropylammonium, trimethylammonium, tetramethylammonium, and imidazolium.
  • any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable.
  • An "isomer" of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.
  • stereoisomer is an isomer in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs.
  • “Enantiomers” are stereoisomers that are mirror images of each other, like left and right hands.
  • Diastereomers are stereoisomers that are not enantiomers.
  • the methods of the present invention have utility for treating and/or preventing glucose-associated conditions, such as diabetes.
  • Non-limiting aspects of the invention include ameliorating disease severity, disease symptoms, and/or the periodicity of recurrence of the disease.
  • Glucose-associated conditions include, but are not limited to, type 1 diabetes (insulin dependent diabetes mellitus or IDDM), type 2 diabetes (non-insulin dependent diabetes mellitus or NIDDM), maturity onset diabetes of the youg (MODY), gestational diabetes, diabetic complications such as metabolic acidoses (e.g., diabetic ketoacidosis (DKA)), carbohydrate and lipid metabolism abnormalities, glucosuria, micro- and macrovascular disease, polyneuropathy and diabetic retinopathy, diabetic nephropathy, insulin resistance, impaired glucose tolerance (or glucose intolerance), obesity, hyperglycemia (elevated blood glucose concentration), hyperinsulinemia, hyperlipidemia, hyperlipoproteinemia, atherosclerosis and hypertension (high blood pressure) related thereto, and various metabolic syndromes.
  • IDDM insulin dependent diabetes mellitus
  • NIDDM non-insulin dependent diabetes mellitus or NIDDM
  • MODY maturity onset diabetes of the youg
  • diabetes e.g
  • Metabolic syndromes include digestive tract diseases such as ulceric or inflammatory disease; congenital or acquired digestion and absorption disorder including malabsorption syndrome; disease caused by loss of a mucosal barrier function of the gut; and protein-losing gastroenteropathy. Ulceric diseases include gastric ulcer, duodenal ulcer, small intestinal ulcer, colonic ulcer and rectal ulcer. Inflammatory diseases include esophagitis, gastritis, duodenitis, enteritis, colitis, Crohn's disease, proctitis, gastrointestinal Behcet, radiation enteritis, radiation colitis, radiation proctitis, enteritis and medicamentosa.
  • Ulceric diseases include gastric ulcer, duodenal ulcer, small intestinal ulcer, colonic ulcer and rectal ulcer.
  • Inflammatory diseases include esophagitis, gastritis, duodenitis, enteritis, colitis, Crohn's disease, proctitis, gastrointestinal Behcet, radiation enteritis, radiation colitis, radiation proctitis, enterit
  • Malabsorption syndrome includes essential malabsorption syndromes such as disaccharide- decomposing enzyme deficiency, glucose-galactose malabsorption, fructose malabsorption; secondary malabsorption syndrome, short gut syndrome, cul-de-sac syndrome; and indigestible malabsorption syndromes such as syndromes associated with resection of the stomach, e.g., dumping syndrome.
  • essential malabsorption syndromes such as disaccharide- decomposing enzyme deficiency, glucose-galactose malabsorption, fructose malabsorption
  • secondary malabsorption syndrome short gut syndrome, cul-de-sac syndrome
  • indigestible malabsorption syndromes such as syndromes associated with resection of the stomach, e.g., dumping syndrome.
  • Other conditions associated with above-normal blood glucose concentration either in an acute or chronic form are also embraced by the invention.
  • the invention also intends to embrace treatment of conditions which would benefit from ⁇ - cell preservation, reduced glucagon levels or increased insulin availability.
  • Diabetes is generally a disease in which the body is unable to produce insulin or does not adequately utilize the insulin it does produce.
  • Insulin is a hormone that facilitates entry of sugars, starches and the like into cells, thereby allowing their conversion into useable energy for the body. In diabetes, therefore, there is a buildup of glucose in the blood due to the inefficient or nonexistent cellular uptake of sugar, starches and the like.
  • Type 2 diabetes is also characterized by progressive beta-cell failure. Type 2 diabetes is also referred to as adult onset diabetes or non-insulin-dependent diabetes (NIDDM).
  • NIDDM non-insulin-dependent diabetes
  • Type 1 diabetes is known to be caused by the selective autoimmune destruction of pancreatic ⁇ -cells, triggered by environmental factors, that leads to a severe state of insulin insufficiency requiring insulin injection therapy and close to constant monitoring to avoid complications.
  • this invention improves upon this type of treatment by replenishing functional ⁇ -cell mass.
  • the methods of this invention may prolong the 'honeymoon period' in the pathogenesis of type-1 diabetes and/or reduce the severity of the disease.
  • a regime that reduces autoimmune mediated destruction of ⁇ -cells e.g. anti- CD3 monoclonal therapy (Chatenoud and Bluestone, 2007)).
  • a regime that reduces autoimmune mediated destruction of ⁇ -cells e.g. anti- CD3 monoclonal therapy (Chatenoud and Bluestone, 2007).
  • Such a strategy could reverse the type-1 diabetes disease process by allowing natural spontaneous ⁇ -cell regeneration (Nir et aL, 2007).
  • One category of subjects to be treated according to the invention are those that demonstrate impaired glucose tolerance (or glucose intolerance), such as but not limited to subjects having or at risk of developing type 2 diabetes. These subjects generally demonstrate an inability to control glucose levels upon eating in comparison to a non-diabetic or non- prediabetic "normal" subject. Subjects at risk of developing type 2 diabetes who demonstrate impaired glucose tolerance are considered to be in a prediabetic state.
  • Glucose tolerance can be measured using glucose challenge tests. There are at least two such tests currently available: the Fasting Plasma Glucose Test (FPG) and the Oral Glucose Tolerance Test (OGTT).
  • FPG Fasting Plasma Glucose Test
  • OGTT Oral Glucose Tolerance Test
  • a FPG blood glucose level between 100-125 mg/dl of blood is indicative of a prediabetic state and an FPG blood glucose level equal to or greater than 126 mg/dl of blood is indicative of diabetes.
  • OGTT measures blood glucose levels two hours after ingestion of a glucose-rich drink following a fasting period.
  • An OGTT blood glucose level between 140-199 mg/dl is indicative of prediabetes, and a level equal to or greater than 200 mg/dl is indicative of diabetes.
  • the presence of glycosylated hemoglobin at levels equal to or greater than 7.0% is also considered an early indicator of the onset of diabetes.
  • Risk factors for type 2 diabetes include obesity, family history of diabetes, prior history of gestational diabetes, impaired glucose tolerance (as discussed above), physical inactivity, and race/ethnicity. African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans and Pacific Islanders are at particularly high risk for type 2 diabetes.
  • Subjects at risk of developing diabetes also may be overweight to the point of being obese.
  • the state of being overweight or obese is defined in terms of the medically recognized body mass index (BMI).
  • BMI body mass index
  • a subject having a BMI of 25 to 29.9 is considered overweight.
  • a subject having a BMI of 30 or more is considered obese.
  • Symptoms associated with diabetes include but are not limited to frequent urination, excessive thirst, extreme hunger, unusual weight loss, increased fatigue, irritability and blurred vision. Diabetes is also associated with other conditions, many of which result from a diabetic state. These include acute metabolic complications such as diabetic ketoacidosis and hyperosmolar coma, and late complications such as circulatory abnormalities, retinopathy, nephropathy, neuropathy and foot ulcers. A more detailed description of the foregoing terms can be obtained from a number of sources known in the art (see, e.g., Harrison's Principles of Experimental Medicine). Thus, the methods of the invention also embrace ameliorating or resolving diabetes-associated conditions such as but not including those recited above.
  • adenine derivatives refers to a class of compounds of the structure: or pharmaceutically acceptable salts, hydrates, solvates, tautomers, or optical isomers thereof, wherein the variables are as defined in the summary section above.
  • adenine derivatives that may be used in accordance with the invention are provided throughout this application.
  • the adenine derivative is 3-methyladenine (3-MA), M)-methyladenine (M5-MA), or 9-methyladenine (9- MA).
  • the effects of methylated adenine analogs on isolated rat islets are consistent with many of these compounds potentiating glucose-induced insulin secretion (see also FIG. IA).
  • the results shown in FIG. IB are consistent with glucose-dependence of 250 ⁇ M 3-MA, M5-MA or 9-MA on potentiating insulin secretion that is equivalent, if not better, than the effect of the GLP-I analog exendin- 4 (5nM).
  • 3-MA was found to potentiate both the 1 st and 2 nd phases of glucose-induced insulin secretion, similar to exendin-4.
  • a dose response of 3-MA, M5-MA or 9-MA in isolated rat islet experiments has been conducted and found to be similar.
  • adenine derivatives were found to significantly potentiate glucose-induced proinsulin biosynthesis at the translational level in rat islets, without affect on basal proinsulin biosynthesis at 3mM glucose (see Example 1). These derivatives did not affect preproinsulin mRNA expression in rat islet ⁇ -cells.
  • Example 3 shows results related to how adenine derivatives exert their glucose dependent effects on ⁇ -cells. Results using real time imaging approaches as described Landa et al. (2005), which is incorporated by reference herein, have found in INS-I cells and rat islet monolayers that 3 -MA rapidly evokes a glucose-dependent increase in cytosolic [CAMP] 1 without significantly affecting cytosolic [Ca 2+ J 1 levels. As such, like GLP-I, 3-MA may operate via elevation of cytosolic [CAMP] 1 .
  • the intracellular [CAMP] 1 can be elevated in ⁇ - cells either (i) via GPCR/G ⁇ s coupling to activate adenylyl cyclase to catalyze the conversion of ATP to [CAMP] 1 and pyrophosphate or (ii) via inhibition of a phosphodiesterase (PDE) that mediates the degradation of [CAMP] 1 .
  • PDE phosphodiesterase
  • the invention also provides methods of using adenine derivatives for the promotion of ⁇ -cell growth and/or survival.
  • Example 4 shows that 3-MA, M)-MA and 9-MA can each promote ⁇ -cell growth and/or survival. These results are consistent with 3-MA, M)-MA and 9-MA each augmenting glucose-induced IRS-2 protein expression in isolated rat islets within 6h (FIG. 5). This is preceded by a correlating increase in phosphorylation of the cAMP- activated transcription factor, CREB, which has been previously shown to be involved in GLP-I mediated regulation of IRS-2 expression in ⁇ -cells (Jhala et al, 2003).
  • one aspect of this invention provides a pharmacological means to promote ⁇ -cell growth and/or survival.
  • the invention also provides methods for accelerating the regeneration ⁇ -cells from endogenous ⁇ -cells.
  • this invention provides for ⁇ -cell neogenesis.
  • this strategy provides methods for increasing the number of ⁇ -cells in vitro that are available for transplantation and derived from isolated human islets, and/or enhance protection of surrogate islet ⁇ -cells during the transplantation process thereby improving graft survival.
  • the treatment in accordance with the methods of this invention provides one or more of the following:- (i) an increase in pancreatic insulin levels relative to the levels measured in the absence of an adenine derivative after administration to a subject with symptoms of diabetes.
  • the compound induces at least about a 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% increase in pancreatic insulin levels in a subject, (ii) A reduction or an absence of symptoms of islet inflammation after administration of an adenine derivative to a subject with symptoms of diabetes, (iii) A decrease in blood glucose levels relative to the levels measured in the absence of an adenine derivative in subjects with symptoms of diabetes.
  • the compounds induce at least about a 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in blood glucose levels.
  • the compounds yield blood glucose levels about or close to the levels commonly observed in a normal subject, (iv) An improvement in glucose tolerance after administration of an adenine derivative. In particular, at least about a 5-95%, 10-90%, 10- 80%, 10-70%, 10-60%, improvement in glucose tolerance, (v) An increase in C-peptide levels relative to the levels measured in the absence of adenine derivatives in subjects with symptoms of diabetes.
  • the compounds induce at least about a 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% increase in C-peptide levels
  • Examples of synthetic approaches that can be taken for the synthesis of adenine derivatives include, (i) starting from a substituted pyrimidine nucleus followed by the imidazole ring construction, (ii) starting from the corresponding imidazole ring, then constructing the pyrimidine ring, and (iii) directing substitution of a preformed purine ring.
  • Direct alkylation of the purine ring can be done using different experimental conditions.
  • One example would be the alkylation of chloropurines with an alkyl halide and sodium hydride and dimethylformamide to obtain a position 9 adenine derivative (Raboisson et ah, 2003, which is incorporated herein by reference).
  • Other methods to produce different adenine derivatives have been reported. Some examples can be found in: Fujii et ah, (1979) and Ukena et ah, (1987), both of which are incorporated by reference herein. iii. Administration Methods
  • Adenine derivatives may be administered, e.g., orally or by injection ⁇ e.g. subcutaneous, intravenous, intraperitoneal, intramuscularly, intravenously, intra-arterially, intra-muscularly, etc.)
  • an adenine derivative may be coated in a material to protect it from the action of acids and other natural conditions which may inactivate it.
  • Pharmaceutically-acceptable carriers include diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials which are well-known in the art. Such preparations may routinely contain salt, buffering agents, preservatives, compatible carriers, and optionally other therapeutic or prophylactic agents.
  • Adenine derivatives may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • Adenine derivatives and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • an adenine derivative may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the percentage of an adenine derivative in the compositions and preparations may be varied.
  • the amount of an adenine derivative in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • the invention also embraces pharmaceutical compositions which are formulated for local administration, such as by implants.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, dextrose, dextrose and sodium chloride, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • Sterile injectable solutions can be prepared by incorporating an adenine derivative in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating an adenine derivative into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., an adenine derivative ) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the agent(s), such as an adenine derivative may be formulated as a pharmaceutical composition or preparation.
  • a pharmaceutical composition comprises the agent(s) and a pharmaceutically-acceptable carrier.
  • a pharmaceutically-acceptable carrier means a non-toxic material that does not interfere with the effectiveness of the biological activity of the agents of the invention.
  • Compounds of the invention may also be formulated for local administration, e.g., for topical administration to the skin or mucosa, for topical administration to the eye, for delivery to the lungs by inhalation, or by incorporation into a biocompatible matrix for controlled release to a specified site over an extended period of time ⁇ e.g. , as an active ingredient in a drug-eluting cardiac stent). In certain cases significant systemic concentrations may also be achieved by these routes of administration ⁇ e.g., via pulmonary or transmucosal delivery).
  • pancreatic islet cells are treated ex vivo with a sufficient amount of an adenine derivative to increase the number of precursor pancreatic ⁇ - cells in the islets prior to implantation into the diabetic or prediabetic patient.
  • an adenine derivative to increase the number of precursor pancreatic ⁇ - cells in the islets prior to implantation into the diabetic or prediabetic patient.
  • following expansion ex vivo the population of precursor pancreatic ⁇ -cells is differentiated in culture prior to implantation by contacting them with at least an adenine derivative.
  • Methods for expanding a population of pancreatic ⁇ -cells in vitro are known in the art (see U.S. 2006/0234373, which is incorporated by reference herein). Upon isolation of the pancreas from a suitable donor, cells are isolated and grown in vitro.
  • the cells which are employed are obtained from tissue samples from mammalian donors including human cadavers, porcine fetuses or another suitable source of pancreatic cells.
  • the donor cells are major histocompatibility matched with the recipient for compatibility whenever human cells are used.
  • Purification of the cells can be accomplished by gradient separation after enzymatic ⁇ e.g., collagenase) digestion of the isolated pancreas.
  • the purified cells may be grown in media containing sufficient nutrients and gastrin/CCK receptor ligand and EGF receptor ligand to permit ⁇ -cell survival and proliferation , thus allowing formation of insulin secreting pancreatic ⁇ -cells.
  • following stimulation the insulin secreting pancreatic ⁇ -cells may be directly expanded in culture prior to being transplanted into a patient in need thereof, or can be transplanted directly following treatment with an adenine derivative
  • Methods of transplantation include transplanting insulin secreting pancreatic ⁇ -cells obtained into a patient in need thereof are also known in the art. For example, certain such methods are described in U.S. 2006/0234373, which is incorporated by reference herein. Such methods include encapsulating the insulin producing cells in a semi-permeable membrane prior to transplantation. Such membranes permit insulin secretion from the encapsulated cells while protecting the cells from immune attack. The optimum number of cells to be transplanted is estimated to be between 10,000 and 20,000 insulin producing ⁇ -cells per kg of the patient. Repeated transplants may be required as necessary to maintain an effective therapeutic number of insulin secreting cells.
  • the transplant recipient can also, according to the invention, be provided with a sufficient amount of an adenine derivative to promote growth, neogenesis, survival, and/or to induce proliferation of the transplanted insulin secreting ⁇ -cells. iv. Dosing
  • Adenine derivatives are administered in effective amounts.
  • an effective amount may vary with the subject's age, condition, and sex, as well as the extent of the disease in the subject (e.g., whether the subject is diabetic or prediabetic) and can be determined by one of skill in the art.
  • the dosage may be adjusted by the individual physician in the event of any complication.
  • An effective amount typically will vary from about 0.001 ⁇ g/kg to about 1000 ⁇ g/kg, from about 0.01 ⁇ g/kg to about 750 ⁇ g/kg, from about 100 ⁇ g/kg to about 500 ⁇ g/kg, from about 1.0 ⁇ g/kg to about 250 ⁇ g/kg, from about 10.0 ⁇ g/kg to about 150 ⁇ g/kg in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above).
  • Other suitable dose ranges include 1 ⁇ g to
  • the amount is less than 10,000 ⁇ g per day with a range of 750 ⁇ g to 9000 ⁇ g per day.
  • the effective amount that is less than 1 mg/kg/day, less than 500 ⁇ g/kg/day, less than
  • ⁇ g/kg/day 250 ⁇ g/kg/day, less than 100 ⁇ g/kg/day, less than 50 ⁇ g/kg/day, less than 25 ⁇ g/kg/day or less than 10 ⁇ g/kg/day. It may alternatively be in the range of 1 ⁇ g/kg/day to 200 ⁇ g/kg/day.
  • the unit dosage is an amount that reduces blood glucose by at least 40% as compared to an untreated subject. In another embodiment, the unit dosage is an amount that reduces blood glucose to a level that is ⁇ 10% of the blood glucose level of a non-diabetic subject.
  • Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation.
  • subjects may be administered two doses daily at approximately 12 hour intervals.
  • the agent is administered once a day.
  • the adenine derivatives may be administered on a routine schedule.
  • a routine schedule refers to a predetermined designated period of time.
  • the routine schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined.
  • routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks therebetween.
  • predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc.
  • the invention provides that the agent(s) may taken orally and that the timing of which is or is not dependent upon food intake.
  • the agent can be taken every morning and/or every evening, regardless of when the subject has eaten or will eat.
  • Clinical efficacy of the treatment may be evaluated by administering an escalating dose of single or combinatorial formulations of the invention to a population of patients suffering from hyperglycemia. Subsequently, patients may be evaluated for the following criteria: fasting and postprandial plasma glucose concentration, postprandial glucose excursion, insulin secretion rate, glycated hemoglobin (HbAIc) levels, oral glucose tolerance test (OGTT).
  • HbAIc glycated hemoglobin
  • OGTT oral glucose tolerance test
  • Improvement in one or more of these clinical parameters would constitute one methods for showing the efficacy of the therapy.
  • an escalating dosage study would identify the optimal dosage required per Kg of subject weight balanced against elevation of cardiac and hepatotoxicity biomarkers.
  • the adenine derivatives of the present invention may also be used in combination therapies.
  • Such a combination therapy would comprise treating a subject with adenine derivatives and one or more other therapies.
  • Non limiting examples of such other therapies include immunosuppressive therapy, hormonal therapy, or one or more additional drug(s) or agent(s) (e.g., other anti-diabetic drugs).
  • additional drugs or agents that may be used in accordance with this invention are provided throughout this application.
  • the nature of the additional drug or agent will depend on which of the glucose-associated conditions the subject has or is at risk of developing. Examples of such additional drugs or agents are given in the summary section above and in U.S.
  • the adenine derivative and the second agent may contact the cells at the same time.
  • contact by an adenine derivative may precede or follow contact by a second agent by intervals ranging from hours (e.g., 1, 2, 3, 4, 5, 6, 8, 12, 15, or 18), days (e.g., 1, 2, 3,
  • weeks e.g., 1, 2, 3, 4, 5, 6, 7, or 8.
  • adenine derivative therapy is "A” and the secondary therapy is "B":
  • adenine derivatives of the present invention administered to a patient will follow general protocols for the administration of pharmaceuticals, taking into account the toxicity, if any, of the drug. It is expected that the treatment cycles would be repeated as necessary.
  • Example 1 Effects of methylated adenine analogs on isolated rat islets.
  • IB shows the glucose- dependence of 250 ⁇ M 3-MA, M5-MA or 9-MA on potentiating insulin secretion, as compared to the GLP-I analog exendin-4 (5nM).
  • isolated rat islets were preincubated in Krebs-Ringer bicarbonate buffer, pH 7.4, containing 20 mM hepes and 0.1% bovine serum albumin (KRBH buffer), at basal 2.8 mM glucose, for 1 h at 37 C. Islets were then incubated for 1 h at 37 C in KRBH buffer supplemented as indicated. Insulin secretion was analyzed by radioimmunoassay (RIA) in an aliquot of the incubation medium.
  • RIA radioimmunoassay
  • Islets were lysed in a 50 mM hepes/ 1% Triton X-100 buffer, pH 8. Islets lysates were also analyzed for insulin content by RIA. Insulin secretion was normalized by islets insulin content, and expressed as the percentage of content.
  • 3-MA 250 ⁇ M was found to potentiate both the 1 st and 2 nd phases of 15mM glucose-induced insulin secretion, similar to exendin-4 (5nM).
  • a dose response of 3-MA, M)-MA or 9-MA in isolated rat islet experiments has been conducted and found to be similar, with a threshold of potentiating 15mM glucose-induced insulin secretion between 20-30 ⁇ M that reaches a maximum at >500 ⁇ M.
  • Near-maximal concentration of 250 ⁇ M were used for most of the pilot in vitro studies to date.
  • Isolated rat islets were perifused in KRBH buffer for 30 min at basal 2.8 mM glucose, followed by 40 min at stimulatory 16.7 mM glucose +/- MAs and 10 min at 2.8 mM glucose. Perifusion was at 1 ml/min rate and 1-ml fractions were collected. Insulin secretion was analyzed by RIA in the fractions.
  • 3-MA, M)-MA and 9-MA were found to potentiate 15mM glucose-induced proinsulin biosynthesis at the translational level in rat islets (2-3 fold), with no affect on basal proinsulin biosynthesis at 3mM glucose. 3-MA did not affect preproinsulin mRNA expression in rat islet ⁇ -cells.
  • isolated rat islets were incubated as for the insulin secretion experiment (see above) plus an additional incubation period of 30 min in KRBH buffer at 16.7 mM glucose in the presence of 100 ⁇ Ci of 3 H-Leucine. Islets were then lysed and radiolabeled pro(insulin) immunoprecipitated with an anti-insulin antibody. Immunoprecipitates were analyzed by polyacrylamide gel electrophoresis and fluorography.
  • Example 2 Intraperitoneal glucose tolerance test results in rat studies.
  • 3-MA was found to increase glucose-induced insulin secretion and improve glucose tolerance in normal rats.
  • Normal Sprague-Dawley rats, -200 g bw were fasted overnight, then subjected to an intraperitoneal glucose tolerance test (IPGTT) (Yaekura et al, 2003), using a 1 mg glucose/g bw dose of glucose.
  • IPGTTs were conducted with 3-MA (30 ⁇ g/g bw) or vehicle control given IP, 15 min prior to the glucose dose.
  • Tail blood samples were collected at the indicated time pints and glucose (FIG. 6A) and insulin levels (FIG. 6B) were subsequently measured.
  • the IPGTT procedure used is based on Yaekura et al, 2003, which is incorporated herein by reference.
  • milrinone a PDE3 inhibitor
  • rolipram a PDE4 inhibitor
  • M)-MA and 9-MA significantly potentiates ⁇ -cell proliferation in both INS-I cells and isolated rat islets at glucose concentrations >8mM when assessed by [ 3 H] thymidine incorporation over a 48h period, as described by Lingohr et al. (2002) and H ⁇ gl et al. (1998), which are both incorporated by reference herein.
  • FIG. 3 shows such an effect at a stimulatory concentration of 1 ImM glucose. No effect of M-MA or 9-MA on ⁇ -cell proliferation at basal glucose was observed. Also M-MA, 9-MA and to a lesser extent 3-MA were found to be protective against cytokine-induced apoptosis.
  • FIG. 4 a preliminary experiment is shown where isolated rat islets are exposed to a cytokine cocktail of interleukin-l ⁇ (IL- l ⁇ , 10ng/ml), tumor necrosis factor- ⁇ (TNF- ⁇ , 50ng/ml) and interferon- ⁇ (IFN- ⁇ , 50ng/ml), at a basal 3mM glucose in the presence or absence of 3MA, M-MA or 9-MA (250 ⁇ M) for 24h.
  • IL- l ⁇ interleukin-l ⁇
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IFN- ⁇ interferon- ⁇
  • FIG 5 shows that 250 ⁇ M 3MA, and especially M-MA and 9-MA, all augment 15mM glucose-induced IRS-2 protein expression in isolated rat islets within 6h. This is preceded by a correlating increase in phosphorylation of the cAMP-activated transcription factor, CREB, which has been previously shown to be involved in GLP-I mediated regulation of IRS-2 expression in ⁇ -cells (Jhala et al, 2003), which is incoporated by reference herein).
  • CREB cAMP-activated transcription factor
  • the 3MA/M-MA/9-MA augmented increase in IRS-2 expression in rat islet ⁇ -cells is associated with decreased expression of the pro-apoptotic genes, Bax, Bad and Bak, but not the anti- apoptotic genes Bcl-2 or BCI-X L (see FIG. 5), which are unchanged relative to a loading control protein, the 85kD subunit of PBK (see FIG. 5).
  • Caspase-3, IRS-2, Bax, Bad, Bak, Bcl-2, BCI-X L and PI3K(p85) levels and CREB phosphorylation were determined by immunoblotting analysis with specific antibodies for each protein.
  • Isolated rat islets or INS-I cells were preincubated for 1 h at 37 C in KRBH buffer, 2.8 mM glucose and then incubated for 6 h in KRBH buffer at 15 mM glucose in the absence or presence of the MAs. Islets were lysed in 50 mM hepes, pH 8/1% Triton X-IOO lysis buffer. Islet lysates were then analyzed by polyacrylamide gel electrophoresis and immunoblotting.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des procédés pour la prévention et le traitement de maladies associées au glucose telles que le diabète utilisant des dérivés d’adénine ayant la formule : ou des sels pharmaceutiquement acceptables, des hydrates, des solvates, des tautomères, ou des isomères optiques de ceux-ci, les variables étant comme présentement défini. La présente invention concerne en outre, à cette fin, des compositions pharmaceutiques, des kits et des articles de fabrication comprenant de tels composés.
PCT/US2009/042095 2008-04-29 2009-04-29 Procédés d’utilisation de dérivés d’adénine pour le traitement du diabète et d’autres troubles WO2010002492A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4881308P 2008-04-29 2008-04-29
US61/048,813 2008-04-29

Publications (1)

Publication Number Publication Date
WO2010002492A1 true WO2010002492A1 (fr) 2010-01-07

Family

ID=41466271

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/042095 WO2010002492A1 (fr) 2008-04-29 2009-04-29 Procédés d’utilisation de dérivés d’adénine pour le traitement du diabète et d’autres troubles

Country Status (1)

Country Link
WO (1) WO2010002492A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3050567A1 (fr) * 2013-09-26 2016-08-03 Energenesis Biomedical Co., Ltd. Composé servant à l'activation de l'ampk et ses utilisations
CN111939161A (zh) * 2013-09-26 2020-11-17 华安医学股份有限公司 活化ampk的化合物及其使用
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6558952B1 (en) * 1992-12-14 2003-05-06 Waratah Pharmaceuticals, Inc. Treatment for diabetes
US20070161582A1 (en) * 2003-08-08 2007-07-12 Dusan Mijikovic Pharmaceutical compositions and methods for metabolic modulation
US20080262088A1 (en) * 2006-12-22 2008-10-23 Wendy Hauck Methods, compounds, and compositions for treating metabolic disorders and diabetes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6558952B1 (en) * 1992-12-14 2003-05-06 Waratah Pharmaceuticals, Inc. Treatment for diabetes
US20070161582A1 (en) * 2003-08-08 2007-07-12 Dusan Mijikovic Pharmaceutical compositions and methods for metabolic modulation
US20080262088A1 (en) * 2006-12-22 2008-10-23 Wendy Hauck Methods, compounds, and compositions for treating metabolic disorders and diabetes

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3050567A1 (fr) * 2013-09-26 2016-08-03 Energenesis Biomedical Co., Ltd. Composé servant à l'activation de l'ampk et ses utilisations
EP3050567A4 (fr) * 2013-09-26 2017-04-05 Energenesis Biomedical Co., Ltd. Composé servant à l'activation de l'ampk et ses utilisations
CN111939161A (zh) * 2013-09-26 2020-11-17 华安医学股份有限公司 活化ampk的化合物及其使用
EP3769766A1 (fr) * 2013-09-26 2021-01-27 Energenesis Biomedical Co., Ltd. Adenine pour activer ampk et ses utilisations médicales
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors

Similar Documents

Publication Publication Date Title
JP6387010B2 (ja) 血中グルコースレベルを制御することによる糖尿病及び関連容態の処置のための組成物、方法及び使用
RU2261096C2 (ru) Способ улучшения передачи сигнала в островках лангерганса при сахарном диабете и его профилактике
RU2367423C2 (ru) Композиции и способы для лечения диабета
EP2707017B1 (fr) Lixisenatide et metformine pour le traitement du diabete de type 2
US20040097411A1 (en) Method of treating left ventricular dysfunction
US9867864B2 (en) Use of somatostatin analogs in control of hypoglycemia
EP1511509A1 (fr) Compositions et procedes de traitement du diabete
ES2878001T3 (es) Composiciones del activador de la glucocinasa para el tratamiento de la diabetes
WO2012130955A1 (fr) Prévention de l'hypoglycémie chez des patients atteints du diabète sucré de type 2
WO2010002492A1 (fr) Procédés d’utilisation de dérivés d’adénine pour le traitement du diabète et d’autres troubles
Shaw et al. Metabolic intervention in surgical patients. An assessment of the effect of somatostatin, ranitidine, naloxone, diclophenac, dipyridamole, or salbutamol infusion on energy and protein kinetics in surgical patients using stable and radioisotopes.
Gerich Somatostatin: Its possible role in carbohydrate homeostasis and the treatment of diabetes mellitus
JPWO2005110394A1 (ja) 糖尿病治療薬
US20190134023A1 (en) Method of Restoring the Incretin Effect
Peuler et al. Sildenafil does not enhance but rather attenuates vasorelaxant effects of antidiabetic agents
CN114423462A (zh) 2型糖尿病的治疗
Hargrove et al. Comparison of the glucose dependency of glucagon-like peptide-1 (7–37) and glyburide in vitro and in vivo
AU2001276672B2 (en) Use of the combination of nicotinic acid or derivatives with riboflavin in the manufacture of a medicament for the treatment of primary headaches
Sugimoto et al. Effects of troglitazone on hepatic and peripheral insulin resistance induced by growth hormone excess in rats
WO2010103040A1 (fr) Activateurs de protéine kinases activées par le 5'-adénosine monophosphate (ampk), destinés au traitement de l'hypertension pulmonaire
AU2001276672A1 (en) Use of the combination of nicotinic acid or derivatives with riboflavin in the manufacture of a medicament for the treatment of primary headaches
US20120225131A1 (en) Methods For Treating Type Diabetes With Brown Adipose Transplants
Keen et al. 2.1. 3. Oral hypoglycaemic drugs
ZA200409490B (en) Compositions and methods for treating diabetes

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09773944

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09773944

Country of ref document: EP

Kind code of ref document: A1