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1.
Bioorg Med Chem Lett ; 25(24): 5767-71, 2015 Dec 15.
Article in English | MEDLINE | ID: mdl-26546218

ABSTRACT

A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.


Subject(s)
Amides/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Pyrans/chemistry , Sulfonamides/chemistry , Animals , Binding Sites , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Dogs , Half-Life , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Molecular Docking Simulation , Protein Structure, Tertiary , Pyrans/chemical synthesis , Pyrans/pharmacokinetics , Rats , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 23(19): 5361-6, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23972441

ABSTRACT

A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.


Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Pyrans/chemical synthesis , Animals , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dogs , Enzyme Activation/drug effects , Glucose Tolerance Test , Haplorhini , Humans , Inhibitory Concentration 50 , Pyrans/chemistry , Pyrans/pharmacology , Rats , Stereoisomerism
3.
J Med Chem ; 53(19): 7251-63, 2010 Oct 14.
Article in English | MEDLINE | ID: mdl-20857914

ABSTRACT

Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC(50) values of 1 and 2 nM and is not active (IC(50) > 25 µM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP(-/-) and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.


Subject(s)
Anti-Obesity Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Carboxypeptidases/antagonists & inhibitors , Phenylalanine/analogs & derivatives , Serine Proteinase Inhibitors/chemical synthesis , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Biological Availability , Blood Proteins/metabolism , Carboxypeptidases/genetics , Drug Design , Humans , Male , Mice , Mice, Knockout , Obesity/drug therapy , Obesity/enzymology , Phenylalanine/chemical synthesis , Phenylalanine/pharmacokinetics , Phenylalanine/pharmacology , Protein Binding , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Stereoisomerism , Structure-Activity Relationship
4.
Eur J Pharmacol ; 623(1-3): 148-54, 2009 Nov 25.
Article in English | MEDLINE | ID: mdl-19765579

ABSTRACT

Inhibition of dipeptidyl peptidase-4 (DPP-4) activity has been shown to improve glycemic control in patients with type 2 diabetes by prolonging and potentiating the actions of incretin hormones. This study is designed to determine the effects of the DPP-4 inhibitor sitagliptin on improving islet function in a mouse model of insulin resistance and insulin secretion defects. ICR mice were pre-treated with high fat diet and a low dose of streptozotocin to induce insulin resistance and impaired insulin secretion, respectively. Diabetic mice were treated with sitagliptin or the sulfonylurea agent glipizide as admixture to high fat diet for ten weeks. Sustained reduction of blood glucose, HbA(1c), circulating glucagon and improvement in oral glucose tolerance were observed in mice treated with sitagliptin. In contrast, glipizide improved glycemic control only during the early weeks and to a lesser degree compared to sitagliptin, and had no effect on circulating glucagon levels or glucose tolerance. The improvement in glycemic control in sitagliptin-treated mice was associated with a significant increase in glucose-dependent insulin secretion in both perfused pancreas and isolated islets. Importantly, in contrast to the lack of effect by glipizide, sitagliptin significantly restored beta and alpha cell mass as well as alpha/beta cell ratio. These data indicate that DPP-4 inhibition by sitagliptin provided better overall improvement of glycemic control compared to glipizide in the high fat diet/streptozotocin induced diabetic mouse model. The ability of sitagliptin to enhance islet cell function may offer insight into the potential for disease modification.


Subject(s)
Blood Glucose/analysis , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors , Glipizide/therapeutic use , Hypoglycemic Agents/therapeutic use , Islets of Langerhans/drug effects , Pyrazines/therapeutic use , Triazoles/therapeutic use , Animals , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 2/physiopathology , Dietary Fats/administration & dosage , Dipeptidyl Peptidase 4 , Glipizide/metabolism , Glucagon/blood , Glucagon-Like Peptide 1/blood , Glycated Hemoglobin/analysis , Hypoglycemic Agents/metabolism , Insulin/blood , Insulin/metabolism , Insulin Secretion , Islets of Langerhans/metabolism , Islets of Langerhans/pathology , Ki-67 Antigen/metabolism , Lipids/blood , Liver/chemistry , Male , Mice , Mice, Inbred ICR , Organ Size , Pyrazines/metabolism , Sitagliptin Phosphate , Triazoles/metabolism , Triglycerides/analysis
6.
J Med Chem ; 51(3): 589-602, 2008 Feb 14.
Article in English | MEDLINE | ID: mdl-18201067

ABSTRACT

A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b- 49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC50 = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.


Subject(s)
Amides/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors , Piperazines/chemical synthesis , Pyrazines/chemical synthesis , Triazoles/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Crystallography, X-Ray , Dipeptidyl Peptidase 4/chemistry , Dogs , Glucose Tolerance Test , Haplorhini , Humans , Male , Mice , Mice, Inbred C57BL , Piperazines/pharmacokinetics , Piperazines/pharmacology , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Triazoles/pharmacokinetics , Triazoles/pharmacology
7.
J Med Chem ; 49(12): 3614-27, 2006 Jun 15.
Article in English | MEDLINE | ID: mdl-16759103

ABSTRACT

A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/metabolism , Hypoglycemic Agents/chemical synthesis , Phenylalanine/analogs & derivatives , Protease Inhibitors/chemical synthesis , Triazoles/chemical synthesis , Administration, Oral , Animals , Biological Availability , Calcium Channels, L-Type/drug effects , Cell Line , Crystallography, X-Ray , Glucose Tolerance Test , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Muscle Proteins/antagonists & inhibitors , Muscle, Skeletal/metabolism , NAV1.5 Voltage-Gated Sodium Channel , Phenylalanine/chemical synthesis , Phenylalanine/chemistry , Phenylalanine/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Rabbits , Sodium Channels , Stereoisomerism , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacology
8.
Diabetes ; 55(6): 1695-704, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16731832

ABSTRACT

Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic beta-cell mass and function. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of sitagliptin (des-fluoro-sitagliptin), on glycemic control and pancreatic beta-cell mass and function in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. Significant and dose-dependent correction of postprandial and fasting hyperglycemia, HbA(1c), and plasma triglyceride and free fatty acid levels were observed in HFD/STZ mice following 2-3 months of chronic therapy. Treatment with des-fluoro-sitagliptin dose dependently increased the number of insulin-positive beta-cells in islets, leading to the normalization of beta-cell mass and beta-cell-to-alpha-cell ratio. In addition, treatment of mice with des-fluoro-sitagliptin, but not glipizide, significantly increased islet insulin content and improved glucose-stimulated insulin secretion in isolated islets. These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of type 2 diabetes by modifying the courses of the disease.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors , Insulin-Secreting Cells/drug effects , Pyrazines/pharmacology , Triazoles/pharmacology , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/metabolism , Disease Models, Animal , Dyslipidemias/drug therapy , Dyslipidemias/metabolism , Glipizide/pharmacology , Hypoglycemic Agents/pharmacology , Immunohistochemistry , Insulin/metabolism , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/physiology , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Islets of Langerhans/pathology , Male , Mice , Mice, Inbred ICR , Pyrazines/chemistry , Sitagliptin Phosphate , Sulfonylurea Compounds/pharmacology , Triazoles/chemistry
9.
Diabetes ; 54(10): 2988-94, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16186403

ABSTRACT

Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidases/antagonists & inhibitors , Dipeptidyl Peptidase 4 , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors , Hypoglycemic Agents , Protease Inhibitors/therapeutic use , Animals , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/physiology , Dogs , Female , Humans , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/toxicity , Isoleucine/analogs & derivatives , Isoleucine/chemistry , Isoleucine/therapeutic use , Isoleucine/toxicity , Isomerism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Protease Inhibitors/toxicity , Rats , Recombinant Proteins/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/therapeutic use , Thiazoles/toxicity
10.
J Med Chem ; 48(1): 141-51, 2005 Jan 13.
Article in English | MEDLINE | ID: mdl-15634008

ABSTRACT

A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/drug effects , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Administration, Oral , Animals , Binding Sites , Biochemistry/methods , Blood Glucose/analysis , Crystallography, X-Ray , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/metabolism , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Glucagon/blood , Glucagon/drug effects , Glucagon-Like Peptide 1 , Glucose Tolerance Test , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Mice , Mice, Inbred C57BL , Models, Molecular , Peptide Fragments/blood , Peptide Fragments/drug effects , Protein Conformation , Protein Precursors/blood , Protein Precursors/drug effects , Pyrazines/pharmacokinetics , Rats , Sitagliptin Phosphate , Structure-Activity Relationship , Triazoles/pharmacokinetics
11.
Proc Natl Acad Sci U S A ; 100(11): 6825-30, 2003 May 27.
Article in English | MEDLINE | ID: mdl-12748388

ABSTRACT

Dipeptidyl peptidase IV (DP-IV), a member of the prolyl oligopeptidase family of peptidases, is involved in the metabolic inactivation of a glucose-dependent insulinotropic hormone, glucagon-like peptide 1 (GLP-1), and other incretin hormones. Here, we investigated the impact of DP-IV deficiency on body weight control and insulin sensitivity in mice. Whereas WT mice displayed accelerated weight gain and hyperinsulinemia when fed a high-fat diet (HFD), mice lacking the gene encoding DP-IV (DP-IV-/-) are refractory to the development of obesity and hyperinsulinemia. Pair-feeding and indirect calorimetry studies indicate that reduced food intake and increased energy expenditure accounted for the resistance to HFD-induced obesity in the DP-IV-/- mice. Ablation of DP-IV also is associated with elevated GLP-1 levels and improved metabolic control in these animals, resulting in improved insulin sensitivity, reduced pancreatic islet hypertrophy, and protection against streptozotocin-induced loss of beta cell mass and hyperglycemia. Together, these observations suggest that chronic deletion of DP-IV gene has significant impact on body weight control and energy homeostasis, providing validation of DP-IV inhibition as a viable therapeutic option for the treatment of metabolic disorders related to diabetes and obesity.


Subject(s)
Dipeptidyl Peptidase 4/metabolism , Genetic Predisposition to Disease , Insulin Resistance , Obesity/genetics , Animals , Base Sequence , DNA Primers , Dipeptidyl Peptidase 4/genetics , Hyperglycemia/chemically induced , Immunohistochemistry , Male , Mice , Reverse Transcriptase Polymerase Chain Reaction , Streptozocin
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