2fjp › Citations

(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: a selective alpha-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

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
J Med Chem 49 3614-27 (2006)
Cited: 57 times
EuropePMC logo PMID: 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.

Articles - 2fjp mentioned but not cited (7)

  1. Ligand deconstruction: Why some fragment binding positions are conserved and others are not. Kozakov D, Hall DR, Jehle S, Luo L, Ochiana SO, Jones EV, Pollastri M, Allen KN, Whitty A, Vajda S. Proc Natl Acad Sci U S A 112 E2585-94 (2015)
  2. Hot spot analysis for driving the development of hits into leads in fragment-based drug discovery. Hall DR, Ngan CH, Zerbe BS, Kozakov D, Vajda S. J Chem Inf Model 52 199-209 (2012)
  3. The good, the bad and the dubious: VHELIBS, a validation helper for ligands and binding sites. Cereto-Massagué A, Ojeda MJ, Joosten RP, Valls C, Mulero M, Salvado MJ, Arola-Arnal A, Arola L, Garcia-Vallvé S, Pujadas G. J Cheminform 5 36 (2013)
  4. Systems pharmacology to investigate the interaction of berberine and other drugs in treating polycystic ovary syndrome. Wang Y, Fu X, Xu J, Wang Q, Kuang H. Sci Rep 6 28089 (2016)
  5. Identification of novel human dipeptidyl peptidase-IV inhibitors of natural origin (part I): virtual screening and activity assays. Guasch L, Ojeda MJ, González-Abuín N, Sala E, Cereto-Massagué A, Mulero M, Valls C, Pinent M, Ardévol A, Garcia-Vallvé S, Pujadas G. PLoS One 7 e44971 (2012)
  6. Identification of novel human dipeptidyl peptidase-IV inhibitors of natural origin (Part II): in silico prediction in antidiabetic extracts. Guasch L, Sala E, Ojeda MJ, Valls C, Bladé C, Mulero M, Blay M, Ardévol A, Garcia-Vallvé S, Pujadas G. PLoS One 7 e44972 (2012)
  7. Synthesis, evaluation and molecular docking of prolyl-fluoropyrrolidine derivatives as dipeptidyl peptidase IV inhibitors. Sharma M, Gupta M, Singh D, Kumar M, Kaur P. Chem Biol Drug Des 82 156-166 (2013)


Reviews citing this publication (5)

  1. Plasma protein binding: from discovery to development. Bohnert T, Gan LS. J Pharm Sci 102 2953-2994 (2013)
  2. Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes. Havale SH, Pal M. Bioorg Med Chem 17 1783-1802 (2009)
  3. Opportunities for structure-based design of protease-directed drugs. Mittl PR, Grütter MG. Curr Opin Struct Biol 16 769-775 (2006)
  4. The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry. Ghosh AK, Brindisi M, Sarkar A. ChemMedChem 13 2351-2373 (2018)
  5. Activity and selectivity cliffs for DPP-IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening. Ojeda-Montes MJ, Gimeno A, Tomas-Hernández S, Cereto-Massagué A, Beltrán-Debón R, Valls C, Mulero M, Pujadas G, Garcia-Vallvé S. Med Res Rev 38 1874-1915 (2018)

Articles citing this publication (45)

  1. The importance of plasma protein binding in drug discovery. Trainor GL. Expert Opin Drug Discov 2 51-64 (2007)
  2. Dipeptidyl peptidase inhibition prevents diastolic dysfunction and reduces myocardial fibrosis in a mouse model of Western diet induced obesity. Bostick B, Habibi J, Ma L, Aroor A, Rehmer N, Hayden MR, Sowers JR. Metabolism 63 1000-1011 (2014)
  3. Inhibition of Dipeptidyl Peptidase-4 Impairs Ventricular Function and Promotes Cardiac Fibrosis in High Fat-Fed Diabetic Mice. Mulvihill EE, Varin EM, Ussher JR, Campbell JE, Bang KW, Abdullah T, Baggio LL, Drucker DJ. Diabetes 65 742-754 (2016)
  4. Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function. Aroor AR, Habibi J, Ford DA, Nistala R, Lastra G, Manrique C, Dunham MM, Ford KD, Thyfault JP, Parks EJ, Sowers JR, Rector RS. Diabetes 64 1988-2001 (2015)
  5. Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of glucagon-like peptide-1 receptor signalling. Takada S, Masaki Y, Kinugawa S, Matsumoto J, Furihata T, Mizushima W, Kadoguchi T, Fukushima A, Homma T, Takahashi M, Harashima S, Matsushima S, Yokota T, Tanaka S, Okita K, Tsutsui H. Cardiovasc Res 111 338-347 (2016)
  6. Prevention of obesity-induced renal injury in male mice by DPP4 inhibition. Nistala R, Habibi J, Lastra G, Manrique C, Aroor AR, Hayden MR, Garro M, Meuth A, Johnson M, Whaley-Connell A, Sowers JR. Endocrinology 155 2266-2276 (2014)
  7. Discovery and pharmacological characterization of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitor. Kato N, Oka M, Murase T, Yoshida M, Sakairi M, Yamashita S, Yasuda Y, Yoshikawa A, Hayashi Y, Makino M, Takeda M, Mirensha Y, Kakigami T. Bioorg Med Chem 19 7221-7227 (2011)
  8. Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors. Edmondson SD, Wei L, Xu J, Shang J, Xu S, Pang J, Chaudhary A, Dean DC, He H, Leiting B, Lyons KA, Patel RA, Patel SB, Scapin G, Wu JK, Beconi MG, Thornberry NA, Weber AE. Bioorg Med Chem Lett 18 2409-2413 (2008)
  9. Discovery of DPP IV inhibitors by pharmacophore modeling and QSAR analysis followed by in silico screening. Al-Masri IM, Mohammad MK, Taha MO. ChemMedChem 3 1763-1779 (2008)
  10. Effects of combination therapy with dipeptidyl peptidase-IV and histone deacetylase inhibitors in the non-obese diabetic mouse model of type 1 diabetes. Cabrera SM, Colvin SC, Tersey SA, Maier B, Nadler JL, Mirmira RG. Clin Exp Immunol 172 375-382 (2013)
  11. The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes. Gallagher EJ, Sun H, Kornhauser C, Tobin-Hess A, Epstein S, Yakar S, LeRoith D. Diabetes Metab Res Rev 30 191-200 (2014)
  12. Plasma levels of DPP4 activity and sDPP4 are dissociated from inflammation in mice and humans. Baggio LL, Varin EM, Koehler JA, Cao X, Lokhnygina Y, Stevens SR, Holman RR, Drucker DJ. Nat Commun 11 3766 (2020)
  13. A substrate-free activity-based protein profiling screen for the discovery of selective PREPL inhibitors. Lone AM, Bachovchin DA, Westwood DB, Speers AE, Spicer TP, Fernandez-Vega V, Chase P, Hodder PS, Rosen H, Cravatt BF, Saghatelian A. J Am Chem Soc 133 11665-11674 (2011)
  14. MK-0626, a selective DPP-4 inhibitor, attenuates hepatic steatosis in ob/ob mice. Ohyama T, Sato K, Yamazaki Y, Hashizume H, Horiguchi N, Kakizaki S, Mori M, Kusano M, Yamada M. World J Gastroenterol 20 16227-16235 (2014)
  15. GPR40 reduces food intake and body weight through GLP-1. Gorski JN, Pachanski MJ, Mane J, Plummer CW, Souza S, Thomas-Fowlkes BS, Ogawa AM, Weinglass AB, Di Salvo J, Cheewatrakoolpong B, Howard AD, Colletti SL, Trujillo ME. Am J Physiol Endocrinol Metab 313 E37-E47 (2017)
  16. Accessing Both Retention and Inversion Pathways in Stereospecific, Nickel-Catalyzed Miyaura Borylations of Allylic Pivalates. Zhou Q, Srinivas HD, Zhang S, Watson MP. J Am Chem Soc 138 11989-11995 (2016)
  17. Discovery of potent, selective, and orally bioavailable oxadiazole-based dipeptidyl peptidase IV inhibitors. Xu J, Wei L, Mathvink RJ, Edmondson SD, Eiermann GJ, He H, Leone JF, Leiting B, Lyons KA, Marsilio F, Patel RA, Patel SB, Petrov A, Scapin G, Wu JK, Thornberry NA, Weber AE. Bioorg Med Chem Lett 16 5373-5377 (2006)
  18. Dramatic lithium chloride effect on the reaction stereocontrol in Zn-mediated asymmetric cinnamylation: highly practical synthesis of β-aryl homoallylic amines. Liu M, Shen A, Sun XW, Deng F, Xu MH, Lin GQ. Chem Commun (Camb) 46 8460-8462 (2010)
  19. Combining MK626, a novel DPP-4 inhibitor, and low-dose monoclonal CD3 antibody for stable remission of new-onset diabetes in mice. Ding L, Gysemans CA, Stangé G, Heremans Y, Yuchi Y, Takiishi T, Korf H, Chintinne M, Carr RD, Heimberg H, Pipeleers D, Mathieu C. PLoS One 9 e107935 (2014)
  20. 3D-QSAR studies on fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors by CoMFA and CoMSIA. Zeng J, Liu G, Tang Y, Jiang H. J Mol Model 13 993-1000 (2007)
  21. DPP-4 inhibition improves early mortality, β cell function, and adipose tissue inflammation in db/db mice fed a diet containing sucrose and linoleic acid. Shirakawa J, Okuyama T, Kyohara M, Yoshida E, Togashi Y, Tajima K, Yamazaki S, Kaji M, Koganei M, Sasaki H, Terauchi Y. Diabetol Metab Syndr 8 16 (2016)
  22. Dipeptidyl peptidase IV inhibitor MK-0626 attenuates pancreatic islet injury in tacrolimus-induced diabetic rats. Jin L, Lim SW, Doh KC, Piao SG, Jin J, Heo SB, Chung BH, Yang CW. PLoS One 9 e100798 (2014)
  23. Stimulation of intestinal growth and function with DPP4 inhibition in a mouse short bowel syndrome model. Sueyoshi R, Woods Ignatoski KM, Okawada M, Hartmann B, Holst J, Teitelbaum DH. Am J Physiol Gastrointest Liver Physiol 307 G410-9 (2014)
  24. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: a potent, selective, orally active dipeptidyl peptidase IV inhibitor. Ammirati MJ, Andrews KM, Boyer DD, Brodeur AM, Danley DE, Doran SD, Hulin B, Liu S, McPherson RK, Orena SJ, Parker JC, Polivkova J, Qiu X, Soglia CB, Treadway JL, VanVolkenburg MA, Wilder DC, Piotrowski DW. Bioorg Med Chem Lett 19 1991-1995 (2009)
  25. Highly enantioselective Mannich reactions with α-aryl silyl ketene acetals and imines. Notte GT, Baxter Vu JM, Leighton JL. Org Lett 13 816-818 (2011)
  26. 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV. Duffy JL, Kirk BA, Wang L, Eiermann GJ, He H, Leiting B, Lyons KA, Patel RA, Patel SB, Petrov A, Scapin G, Wu JK, Thornberry NA, Weber AE. Bioorg Med Chem Lett 17 2879-2885 (2007)
  27. [(S)-gamma-(4-Aryl-1-piperazinyl)-l-prolyl]thiazolidines as a novel series of highly potent and long-lasting DPP-IV inhibitors. Yoshida T, Sakashita H, Akahoshi F, Hayashi Y. Bioorg Med Chem Lett 17 2618-2621 (2007)
  28. 4-arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV. Kaelin DE, Smenton AL, Eiermann GJ, He H, Leiting B, Lyons KA, Patel RA, Patel SB, Petrov A, Scapin G, Wu JK, Thornberry NA, Weber AE, Duffy JL. Bioorg Med Chem Lett 17 5806-5811 (2007)
  29. Aminopiperidine-fused imidazoles as dipeptidyl peptidase-IV inhibitors. 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. Bioorg Med Chem Lett 19 4097-4101 (2009)
  30. Discovery of 3-aminopiperidines as potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitors. Cox JM, Harper B, Mastracchio A, Leiting B, Sinha Roy R, Patel RA, Wu JK, Lyons KA, He H, Xu S, Zhu B, Thornberry NA, Weber AE, Edmondson SD. Bioorg Med Chem Lett 17 4579-4583 (2007)
  31. Discovery of new binding elements in DPP-4 inhibition and their applications in novel DPP-4 inhibitor design. Liang GB, Qian X, Biftu T, Singh S, Gao YD, Scapin G, Patel S, Leiting B, Patel R, Wu J, Zhang X, Thornberry NA, Weber AE. Bioorg Med Chem Lett 18 3706-3710 (2008)
  32. Identification of diverse dipeptidyl peptidase IV inhibitors via structure-based virtual screening. Li C, Lu W, Lu C, Xiao W, Shen X, Huang J, Liu G, Tang Y. J Mol Model 18 4033-4042 (2012)
  33. Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling. Rea D, Van Elzen R, De Winter H, Van Goethem S, Landuyt B, Luyten W, Schoofs L, Van Der Veken P, Augustyns K, De Meester I, Fülöp V, Lambeir AM. Eur J Med Chem 139 482-491 (2017)
  34. CoMFA and CoMSIA of diverse pyrrolidine analogues as dipeptidyl peptidase IV inhibitors: active site requirements. Murugesan V, Sethi N, Prabhakar YS, Katti SB. Mol Divers 15 457-466 (2011)
  35. Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor. Nojima H, Kanou K, Terashi G, Takeda-Shitaka M, Inoue G, Atsuda K, Itoh C, Iguchi C, Matsubara H. BMC Struct Biol 16 11 (2016)
  36. DPP IV inhibitor suppresses STZ-induced islets injury dependent on activation of the IGFR/Akt/mTOR signaling pathways by GLP-1 in monkeys. Zhang Y, Chen Y, Cheng J, Guo Z, Lu Y, Tian B. Biochem Biophys Res Commun 456 139-144 (2015)
  37. MK-626, a dipeptidyl peptidase-4 inhibitor, does not improve the hyperglycemia or hyperinsulinemia of nonobese diabetic MKR mice. Bhattacharjee A, Allister EM, Wheeler MB. Can J Physiol Pharmacol 90 663-668 (2012)
  38. Potent oxazolidinone antibacterials with heteroaromatic C-ring substructure. Suzuki H, Utsunomiya I, Shudo K, Fujimura T, Tsuji M, Kato I, Aoki T, Ino A, Iwaki T. ACS Med Chem Lett 4 1074-1078 (2013)
  39. Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin. Zhao B, Sensintaffar J, Bian Z, Belmar J, Lee T, Olejniczak ET, Fesik SW. Bioorg Med Chem 25 3087-3092 (2017)
  40. Synthesis, evaluation and molecular docking of thiazolopyrimidine derivatives as dipeptidyl peptidase IV inhibitors. Sharma M, Gupta M, Singh D, Kumar M, Kaur P. Chem Biol Drug Des 80 918-928 (2012)
  41. Dipeptidyl dipeptidase-4 inhibitor recovered ischemia through an increase in vasculogenic endothelial progenitor cells and regeneration-associated cells in diet-induced obese mice. Salybekov AA, Masuda H, Miyazaki K, Sheng Y, Sato A, Shizuno T, Iida Y, Okada Y, Asahara T. PLoS One 14 e0205477 (2019)
  42. New leads for DPP IV inhibition: structure-based pharmacophore mapping and virtual screening study. Almasri IM, Taha MO, Mohammad MK. Arch Pharm Res 36 1326-1337 (2013)
  43. Predicting the DPP-IV inhibitory activity pIC₅₀ based on their physicochemical properties. Gu T, Yang X, Li M, Wu M, Su Q, Lu W, Zhang Y. Biomed Res Int 2013 798743 (2013)
  44. Synthesis of 3-fluoropyrrolidines and 4-fluoropyrrolidin-2-ones from allylic fluorides. Combettes LE, Schuler M, Patel R, Bonillo B, Odell B, Thompson AL, Claridge TD, Gouverneur V. Chemistry 18 13126-13132 (2012)
  45. A facile, practical and metal-free microwave-assisted protocol for mono- and bis-[1,2,4]triazolo[1,5-a]pyridines synthesis utilizing 1-amino-2-imino-pyridine derivatives as versatile precursors. Ibrahim HM, Behbehani H, Ahmed Arafa WA. RSC Adv 10 15554-15572 (2020)


Quick links