Roy RS

References (9)

Title : Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity - Zhou_2010_J.Med.Chem_53_7251
Author(s) : Zhou C , Garcia-Calvo M , Pinto S , Lombardo M , Feng Z , Bender K , Pryor KD , Bhatt UR , Chabin RM , Geissler WM , Shen Z , Tong X , Zhang Z , Wong KK , Roy RS , Chapman KT , Yang L , Xiong Y
Ref : Journal of Medicinal Chemistry , 53 :7251 , 2010
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 microM) 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.
ESTHER : Zhou_2010_J.Med.Chem_53_7251
PubMedSearch : Zhou_2010_J.Med.Chem_53_7251
PubMedID: 20857914
Gene_locus related to this paper: human-PRCP

Title : Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes - Mu_2009_Eur.J.Pharmacol_623_148
Author(s) : Mu J , Petrov A , Eiermann GJ , Woods J , Zhou YP , Li Z , Zycband E , Feng Y , Zhu L , Roy RS , Howard AD , Li C , Thornberry NA , Zhang BB
Ref : European Journal of Pharmacology , 623 :148 , 2009
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.
ESTHER : Mu_2009_Eur.J.Pharmacol_623_148
PubMedSearch : Mu_2009_Eur.J.Pharmacol_623_148
PubMedID: 19765579

Title : Aminopiperidine-fused imidazoles as dipeptidyl peptidase-IV inhibitors - Edmondson_2009_Bioorg.Med.Chem.Lett_19_4097
Author(s) : Edmondson SD , Mastracchio A , Cox JM , Eiermann GJ , He H , Lyons KA , Patel RA , Patel SB , Petrov A , Scapin G , Wu JK , Xu S , Zhu B , Thornberry NA , Roy RS , Weber AE
Ref : Bioorganic & Medicinal Chemistry Lett , 19 :4097 , 2009
Abstract : A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.
ESTHER : Edmondson_2009_Bioorg.Med.Chem.Lett_19_4097
PubMedSearch : Edmondson_2009_Bioorg.Med.Chem.Lett_19_4097
PubMedID: 19539471
Gene_locus related to this paper: human-DPP4

Title : Discovery of potent and selective dipeptidyl peptidase IV inhibitors derived from beta-aminoamides bearing subsituted triazolopiperazines - Kim_2008_J.Med.Chem_51_589
Author(s) : Kim D , Kowalchick JE , Brockunier LL , Parmee ER , Eiermann GJ , Fisher MH , He H , Leiting B , Lyons K , Scapin G , Patel SB , Petrov A , Pryor KD , Roy RS , Wu JK , Zhang X , Wyvratt MJ , Zhang BB , Zhu L , Thornberry NA , Weber AE
Ref : Journal of Medicinal Chemistry , 51 :589 , 2008
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.
ESTHER : Kim_2008_J.Med.Chem_51_589
PubMedSearch : Kim_2008_J.Med.Chem_51_589
PubMedID: 18201067

Title : Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes - Mu_2006_Diabetes_55_1695
Author(s) : Mu J , Woods J , Zhou YP , Roy RS , Li Z , Zycband E , Feng Y , Zhu L , Li C , Howard AD , Moller DE , Thornberry NA , Zhang BB
Ref : Diabetes , 55 :1695 , 2006
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.
ESTHER : Mu_2006_Diabetes_55_1695
PubMedSearch : Mu_2006_Diabetes_55_1695
PubMedID: 16731832

Title : (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]tr iazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: a selective alpha-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes - Edmondson_2006_J.Med.Chem_49_3614
Author(s) : Edmondson SD , Mastracchio A , Mathvink RJ , He J , Harper B , Park YJ , Beconi M , Di Salvo J , Eiermann GJ , He H , Leiting B , Leone JF , Levorse DA , Lyons K , Patel RA , Patel SB , Petrov A , Scapin G , Shang J , Roy RS , Smith A , Wu JK , Xu S , Zhu B , Thornberry NA , Weber AE
Ref : Journal of Medicinal Chemistry , 49 :3614 , 2006
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]tr iazolo[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.
ESTHER : Edmondson_2006_J.Med.Chem_49_3614
PubMedSearch : Edmondson_2006_J.Med.Chem_49_3614
PubMedID: 16759103
Gene_locus related to this paper: human-DPP4

Title : Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9 - Lankas_2005_Diabetes_54_2988
Author(s) : Lankas GR , Leiting B , Roy RS , Eiermann GJ , Beconi MG , Biftu T , Chan CC , Edmondson S , Feeney WP , He H , Ippolito DE , Kim D , Lyons KA , Ok HO , Patel RA , Petrov AN , Pryor KA , Qian X , Reigle L , Woods A , Wu JK , Zaller D , Zhang X , Zhu L , Weber AE , Thornberry NA
Ref : Diabetes , 54 :2988 , 2005
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.
ESTHER : Lankas_2005_Diabetes_54_2988
PubMedSearch : Lankas_2005_Diabetes_54_2988
PubMedID: 16186403

Title : (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: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes - Kim_2005_J.Med.Chem_48_141
Author(s) : Kim D , Wang L , Beconi M , Eiermann GJ , Fisher MH , He H , Hickey GJ , Kowalchick JE , Leiting B , Lyons K , Marsilio F , McCann ME , Patel RA , Petrov A , Scapin G , Patel SB , Roy RS , Wu JK , Wyvratt MJ , Zhang BB , Zhu L , Thornberry NA , Weber AE
Ref : Journal of Medicinal Chemistry , 48 :141 , 2005
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.
ESTHER : Kim_2005_J.Med.Chem_48_141
PubMedSearch : Kim_2005_J.Med.Chem_48_141
PubMedID: 15634008
Gene_locus related to this paper: human-DPP4

Title : Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance - Conarello_2003_Proc.Natl.Acad.Sci.U.S.A_100_6825
Author(s) : Conarello SL , Li Z , Ronan J , Roy RS , Zhu L , Jiang G , Liu F , Woods J , Zycband E , Moller DE , Thornberry NA , Zhang BB
Ref : Proc Natl Acad Sci U S A , 100 :6825 , 2003
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.
ESTHER : Conarello_2003_Proc.Natl.Acad.Sci.U.S.A_100_6825
PubMedSearch : Conarello_2003_Proc.Natl.Acad.Sci.U.S.A_100_6825
PubMedID: 12748388
Gene_locus related to this paper: mouse-dpp4