Nancy A Thornberry

Publications (54)231.42 Total impact

• Article: The roles of voltage-gated potassium channels Kv2.1 and Kv2.2 in the regulation of insulin and somatostatin release from pancreatic islets.

  Xiaoyan Nina Li, James Herrington, Aleksandr Petrov, Lan Ge, George Eiermann, Yusheng Xiong, Mette V Jensen, Hans E Hohmeier, Christopher B Newgard, Maria L Garcia, Michael Wagner, Bei B Zhang, Nancy A Thornberry, Andrew D Howard, Gregory J Kaczorowski, Yun-Ping Zhou
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  ABSTRACT: The voltage-gated potassium channels Kv2.1 and Kv2.2 are highly expressed in pancreatic islets, yet their contribution to islet hormone secretion are not fully understood. Here we investigate the role of Kv2 channels in pancreatic islets using a combination of genetic and pharmacological approaches. Pancreatic β-cells from Kv2.1(-/-) mice possess reduced Kv current and display greater glucose-stimulated insulin secretion (GSIS) relative to wild-type β-cells. Inhibition of Kv2.x channels with selective peptidyl (GxTX-1E) or small molecule (RY796) inhibitors enhances GSIS in isolated wild-type mouse and human islets, but not in islets from Kv2.1(-/-) mice. However, in wild-type mice neither inhibitor improved glucose tolerance in vivo. GxTX-1E and RY796 enhanced somatostatin release in isolated human and mouse islets and in situ perfused pancreata from wild-type and Kv2.1-/- mice. Kv2.2 silencing in mouse islets by adenovirus-shRNA specifically enhanced islet somatostatin, but not insulin, secretion. In mice lacking somatostatin receptor 5, GxTX-1E stimulated insulin secretion and improved glucose tolerance. Collectively, these data show that Kv2.1 regulates insulin secretion in β-cells and Kv2.2 modulates somatostatin release in δ-cells. Development of selective Kv2.1 inhibitors without cross inhibition of Kv2.2 may provide new avenues to promote GSIS for the treatment of type 2 diabetes.
  Journal of Pharmacology and Experimental Therapeutics 11/2012; · 3.83 Impact Factor
• Article: Bombesin receptor subtype-3 (BRS-3) regulates glucose-stimulated insulin secretion in pancreatic islets across multiple species.

  Yue Feng, Xiao-Ming Guan, Jing Li, Joseph M Metzger, Yonghua Zhu, Kirstine Juhl, Bei B Zhang, Nancy A Thornberry, Marc L Reitman, Yun-Ping Zhou
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  ABSTRACT: Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, and BRS-3 agonism is being explored as a possible therapy for obesity. Here we study the role of BRS-3 in the regulation of glucose-stimulated insulin secretion (GSIS) and glucose homeostasis. We quantified BRS-3 mRNA in pancreatic islets from multiple species and examined the acute effects of Bag-1, a selective BRS-3 agonist, on GSIS in mouse, rat, and human islets, and on oral glucose tolerance in mice. BRS-3 is highly expressed in human, mouse, rhesus, and dog (but not rat) pancreatic islets and in rodent insulinoma cell lines (INS-1 832/3 and MIN6). Silencing BRS-3 with small interfering RNA or pharmacological blockade with a BRS-3 antagonist, Bantag-1, reduced GSIS in 832/3 cells. In contrast, the BRS-3 agonist (Bag-1) increased GSIS in 832/3 and MIN6 cells. The augmentation of GSIS by Bag-1 was completely blocked by U73122, a phospholipase C inhibitor. Bag-1 also enhanced GSIS in islets isolated from wild-type, but not Brs3 knockout mice. In vivo, Bag-1 reduced glucose levels during oral glucose tolerance test in a BRS-3-dependent manner. BRS-3 agonists also increased GSIS in human islets. These results identify a potential role for BRS-3 in islet physiology, with agonism directly promoting GSIS. Thus, in addition to its potential role in the treatment of obesity, BRS-3 may also regulate blood glucose levels and have a role in the treatment of diabetes mellitus.
  Endocrinology 08/2011; 152(11):4106-15. · 4.46 Impact Factor
• Article: Synthesis and evaluation of [(1R)-1-amino-2-(2,5-difluorophenyl)ethyl]cyclohexanes and 4-[(1R)-1-amino-2-(2,5-difluorophenyl)ethyl]piperidines as DPP-4 inhibitors.

  Ping Chen, Charles G Caldwell, Wallace Ashton, Joseph K Wu, Huaibing He, Kathryn A Lyons, Nancy A Thornberry, Ann E Weber
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  ABSTRACT: A series of 4-amino cyclohexanes and 4-substituted piperidines were prepared and evaluated for inhibition of DPP-4. Analog 20q displayed both good DPP-4 potency and selectivity against other proteases, while derivative 20k displayed long half life and modest oral bioavailability in rat. The most potent analog, 3-(5-aminocarbonylpyridyl piperidine 53j, displayed excellent DPP-4 activity with good selectivity versus other proline enzymes.
  Bioorganic & medicinal chemistry letters 01/2011; 21(6):1880-6. · 2.65 Impact Factor
• Article: Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes.

  James Mu, Aleksandr Petrov, George J Eiermann, John Woods, Yun-Ping Zhou, Zhihua Li, Emanuel Zycband, Yue Feng, Lan Zhu, Ranabir Sinha Roy, Andrew D Howard, Cai Li, Nancy A Thornberry, Bei B Zhang
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  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.
  European journal of pharmacology 09/2009; 623(1-3):148-54. · 2.59 Impact Factor
• Article: Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4).

  Nancy A Thornberry, Baptist Gallwitz
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  ABSTRACT: Dipeptidyl-peptidase IV (DPP-4) inhibitors inhibit the degradation of the incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The first available DPP-4 inhibitors are sitagliptin and vildagliptin. These compounds are orally active and have been shown to be efficacious and well tolerated. Two additional DPP-4 inhibitors are under review, and there are several others in clinical development. This article gives an overview on the mechanism of action of DPP-4 inhibitors and focuses on their development and their important physiological actions with regard to the treatment of type 2 diabetes.
  Best practice & research. Clinical endocrinology & metabolism 08/2009; 23(4):479-86. · 3.89 Impact Factor
• Article: Aminopiperidine-fused imidazoles as dipeptidyl peptidase-IV inhibitors.

  Scott D Edmondson, Anthony Mastracchio, Jason M Cox, George J Eiermann, Huaibing He, Kathryn A Lyons, Reshma A Patel, Sangita B Patel, Aleksandr Petrov, Giovanna Scapin, Joseph K Wu, Shiyao Xu, Bing Zhu, Nancy A Thornberry, Ranabir Sinha Roy, Ann E Weber
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  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.
  Bioorganic & medicinal chemistry letters 07/2009; 19(15):4097-101. · 2.65 Impact Factor
• Article: Discovery of new binding elements in DPP-4 inhibition and their applications in novel DPP-4 inhibitor design.

  Gui-Bai Liang, Xiaoxia Qian, Tesfaye Biftu, Suresh Singh, Ying-Duo Gao, Giovanna Scapin, Sangita Patel, Barbara Leiting, Reshma Patel, Joseph Wu, Xiaoping Zhang, Nancy A Thornberry, Ann E Weber
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  ABSTRACT: Probing with tool molecules, and by modeling and X-ray crystallography the binding modes of two structurally distinct series of DPP-4 inhibitors led to the discovery of a rare aromatic fluorine H-bond and the spatial requirement for better biaryl binding in the DPP-4 enzyme active site. These newly found binding elements were successfully incorporated into novel DPP-4 inhibitors.
  Bioorganic & medicinal chemistry letters 07/2008; 18(13):3706-10. · 2.65 Impact Factor
• Source

  Available from: Aleksandr Petrov

  Article: Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice.

  Carina P Tan, Yue Feng, Yun-Ping Zhou, George J Eiermann, Aleksandr Petrov, Changyou Zhou, Songnian Lin, Gino Salituro, Peter Meinke, Ralph Mosley, Taro E Akiyama, Monica Einstein, Sanjeev Kumar, Joel P Berger, Sander G Mills, Nancy A Thornberry, Lihu Yang, Andrew D Howard
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  ABSTRACT: Acute activation of G protein-coupled receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate whether activation of GPR40 would be beneficial for the treatment of type 2 diabetes, since chronic exposure to FFAs impairs islet function. We sought to evaluate the specific role of GPR40 in islets and its potential as a therapeutic target using compounds that specifically activate GPR40. We developed a series of GPR40-selective small-molecule agonists and studied their acute and chronic effects on glucose-dependent insulin secretion (GDIS) in isolated islets, as well as effects on blood glucose levels during intraperitoneal glucose tolerance tests in wild-type and GPR40 knockout mice (GPR40(-/-)). Small-molecule GPR40 agonists significantly enhanced GDIS in isolated islets and improved glucose tolerance in wild-type mice but not in GPR40(-/-) mice. While a 72-h exposure to FFAs in tissue culture significantly impaired GDIS in islets from both wild-type and GPR40(-/-) mice, similar exposure to the GPR40 agonist did not impair GDIS in islets from wild-type mice. Furthermore, the GPR40 agonist enhanced insulin secretion in perfused pancreata from neonatal streptozotocin-induced diabetic rats and improved glucose levels in mice with high-fat diet-induced obesity acutely and chronically. GPR40 does not mediate the chronic toxic effects of FFAs on islet function. Pharmacological activation of GPR40 may potentiate GDIS in humans and be beneficial for overall glucose control in patients with type 2 diabetes.
  Diabetes 06/2008; 57(8):2211-9. · 8.29 Impact Factor
• Article: Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors.

  Scott D Edmondson, Lan Wei, Jinyou Xu, Jackie Shang, Shiyao Xu, Jianmei Pang, Ashok Chaudhary, Dennis C Dean, Huaibing He, Barbara Leiting, Kathryn A Lyons, Reshma A Patel, Sangita B Patel, Giovanna Scapin, Joseph K Wu, Maria G Beconi, Nancy A Thornberry, Ann E Weber
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  ABSTRACT: The synthesis, selectivity, rat pharmacokinetic profile, and drug metabolism profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.
  Bioorganic & medicinal chemistry letters 05/2008; 18(7):2409-13. · 2.65 Impact Factor
• Article: Identification of glucose-dependant insulin secretion targets in pancreatic beta cells by combining defined-mechanism compound library screening and siRNA gene silencing.

  Weizhen Wu, Jin Shang, Yue Feng, Chris M Thompson, Sarah Horwitz, John R Thompson, Euan D MacIntyre, Nancy A Thornberry, Kevin Chapman, Yun-Ping Zhou, Andrew D Howard, Jing Li
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  ABSTRACT: Identification and validation of novel drug targets continues to be a major bottleneck in drug development, particularly for polygenic complex diseases such as type 2 diabetes. Here, the authors describe an approach that allows researchers to rapidly identify and validate potential drug targets by combining chemical tools and RNA interference technology. As a proof-of-concept study, the known mechanism Sigma LOPAC library was used to screen for glucose-dependent insulin secretion (GDIS) in INS-1 832/13 cells. In addition to several mechanisms that are known to regulate GDIS (such as cyclic adenosine monophosphate-specific phosphodiesterases, adrenoceptors, and Ca(2+) channels), the authors find that several of the dopamine receptor (DRD) antagonists significantly enhance GDIS, whereas DRD agonists profoundly inhibit GDIS. Subsequent siRNA studies in the same cell line indicate that knockdown of DRD2 enhanced GDIS. Furthermore, selective DRD2 antagonists and agonists also enhance or suppress, respectively, GDIS in isolated rat islets. The data support that the approach described here offers a rapid and effective way for target identification and validation.
  Journal of Biomolecular Screening 03/2008; 13(2):128-34. · 2.05 Impact Factor
• Article: Discovery of potent and selective dipeptidyl peptidase IV inhibitors derived from beta-aminoamides bearing subsituted triazolopiperazines.

  Dooseop Kim, Jennifer E Kowalchick, Linda L Brockunier, Emma R Parmee, George J Eiermann, Michael H Fisher, Huaibing He, Barbara Leiting, Kathryn Lyons, Giovanna Scapin, [......], Aleksandr Petrov, Kellyann D Pryor, Ranabir Sinha Roy, Joseph K Wu, Xiaoping Zhang, Matthew J Wyvratt, Bei B Zhang, Lan Zhu, Nancy A Thornberry, Ann E Weber
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  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.
  Journal of Medicinal Chemistry 03/2008; 51(3):589-602. · 5.25 Impact Factor
• Article: Discovery of Potent and Selective Dipeptidyl Peptidase IV Inhibitors Derived from β-Aminoamides Bearing Subsituted Triazolopiperazines†

  Dooseop Kim, Jennifer E. Kowalchick, Linda L. Brockunier, Emma R. Parmee, George J. Eiermann, Michael H. Fisher, Huaibing He, Barbara Leiting, Kathryn Lyons, Giovanna Scapin, [......], Aleksandr Petrov, KellyAnn D. Pryor, Ranabir Sinha Roy, Joseph K. Wu, Xiaoping Zhang, Matthew J. Wyvratt, Bei B. Zhang, Lan Zhu, Nancy A. Thornberry, Ann E. Weber
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  ABSTRACT: A series of β-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.
  01/2008;
• Article: Design, synthesis, and biological evaluation of triazolopiperazine-based beta-amino amides as potent, orally active dipeptidyl peptidase IV (DPP-4) inhibitors.

  Jennifer E Kowalchick, Barbara Leiting, KellyAnn D Pryor, Frank Marsilio, Joseph K Wu, Huaibing He, Kathryn A Lyons, George J Eiermann, Aleksandr Petrov, Giovanna Scapin, Reshma A Patel, Nancy A Thornberry, Ann E Weber, Dooseop Kim
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  ABSTRACT: Various beta-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good overall pharmacokinetic profiles in preclinical species. Moreover, in vivo efficacy in an oral glucose tolerance test in lean mice is demonstrated.
  Bioorganic & Medicinal Chemistry Letters 12/2007; 17(21):5934-9. · 2.55 Impact Factor
• Article: 4-arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV.

  David E Kaelin, Abigail L Smenton, George J Eiermann, Huaibing He, Barbara Leiting, Kathryn A Lyons, Reshma A Patel, Sangita B Patel, Alexsandr Petrov, Giovanna Scapin, Joseph K Wu, Nancy A Thornberry, Ann E Weber, Joseph L Duffy
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  ABSTRACT: A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC(50)=4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species. Evaluation of 28 in an oral glucose tolerance test demonstrated that this compound effectively reduced glucose excursion in lean mice.
  Bioorganic & Medicinal Chemistry Letters 12/2007; 17(21):5806-11. · 2.55 Impact Factor
• Article: Imidazopiperidine amides as dipeptidyl peptidase IV inhibitors for the treatment of diabetes.

  Ping Chen, Charles G Caldwell, Robert J Mathvink, Barbara Leiting, Frank Marsilio, Reshma A Patel, Joseph K Wu, Huaibing He, Kathryn A Lyons, Nancy A Thornberry, Ann E Weber
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  ABSTRACT: A series of substituted imidazopiperidine amides has been prepared and evaluated for inhibition of dipeptidyl peptidase IV (DPP-4). Substitution at the 1- and 3-positions produced increased selectivity for DPP-4 relative to DPP-8 and DPP-9. Compounds in this series had IC(50) values as low as 5.8 nM for inhibition of DPP-4.
  Bioorganic & Medicinal Chemistry Letters 12/2007; 17(21):5853-7. · 2.55 Impact Factor
• Article: Discovery of 3-aminopiperidines as potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitors.

  Jason M Cox, Bart Harper, Anthony Mastracchio, Barbara Leiting, Ranabir Sinha Roy, Reshma A Patel, Joseph K Wu, Kathryn A Lyons, Huaibing He, Shiyao Xu, Bing Zhu, Nancy A Thornberry, Ann E Weber, Scott D Edmondson
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  ABSTRACT: Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 inhibitors were further evaluated for their hERG potassium channel, calcium channel, Cyp2D6, and pharmacokinetic profiles.
  Bioorganic & Medicinal Chemistry Letters 09/2007; 17(16):4579-83. · 2.55 Impact Factor
• Article: Modeling assisted rational design of novel, potent, and selective pyrrolopyrimidine DPP-4 inhibitors.

  Ying-Duo Gao, Dennis Feng, Robert P Sheridan, Giovanna Scapin, Sangita B Patel, Joseph K Wu, Xiaoping Zhang, Ranabir Sinha-Roy, Nancy A Thornberry, Ann E Weber, Tesfaye Biftu
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  ABSTRACT: Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4.
  Bioorganic & Medicinal Chemistry Letters 08/2007; 17(14):3877-9. · 2.55 Impact Factor
• Article: Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin.

  Tesfaye Biftu, Giovanna Scapin, Suresh Singh, Dennis Feng, Joe W Becker, George Eiermann, Huaibing He, Kathy Lyons, Sangita Patel, Aleksandr Petrov, Ranabir Sinha-Roy, Bei Zhang, Joseph Wu, Xiaoping Zhang, George A Doss, Nancy A Thornberry, Ann E Weber
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  ABSTRACT: Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile.
  Bioorganic & Medicinal Chemistry Letters 07/2007; 17(12):3384-7. · 2.55 Impact Factor
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  Available from: 124.42.15.59

  Article: Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: close analogs of JANUVIA (sitagliptin phosphate).

  Dooseop Kim, Jennifer E Kowalchick, Scott D Edmondson, Anthony Mastracchio, Jinyou Xu, George J Eiermann, Barbara Leiting, Joseph K Wu, KellyAnn D Pryor, Reshma A Patel, Huaibing He, Kathryn A Lyons, Nancy A Thornberry, Ann E Weber
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  ABSTRACT: A series of beta-aminoamides bearing triazolopiperazines has been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. Efforts at optimization of the beta-aminoamide series, which ultimately led to the discovery of JANUVIA (sitagliptin phosphate, compound 1), are described.
  Bioorganic & Medicinal Chemistry Letters 07/2007; 17(12):3373-7. · 2.55 Impact Factor
• Article: 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV.

  Joseph L Duffy, Brian A Kirk, Liping Wang, George J Eiermann, Huaibing He, Barbara Leiting, Kathryn A Lyons, Reshma A Patel, Sangita B Patel, Alexsandr Petrov, Giovanna Scapin, Joseph K Wu, Nancy A Thornberry, Ann E Weber
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  ABSTRACT: A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC(50)=28nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active site is presented.
  Bioorganic & Medicinal Chemistry Letters 06/2007; 17(10):2879-85. · 2.55 Impact Factor