Pei Zhonghua, Li Xiaofeng, Longenecker Kenton, von Geldern Thomas W, Wiedeman Paul E, Lubben Thomas H, Zinker Bradley A, Stewart Kent, Ballaron Stephen J, Stashko Michael A, Mika Amanda K, Beno David W A, Long Michelle, Wells Heidi, Kempf-Grote Anita J, Madar David J, McDermott Todd S, Bhagavatula Lakshmi, Fickes Michael G, Pireh Daisy, Solomon Larry R, Lake Marc R, Edalji Rohinton, Fry Elizabeth H, Sham Hing L, Trevillyan James M
Department of Exploratory Pharmacokinetics and Pharmaceutics, Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA.
J Med Chem. 2006 Jun 15;49(12):3520-35. doi: 10.1021/jm051283e.
A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
一系列（5-取代吡咯烷基-2-羰基）-2-氰基吡咯烷（C5-Pro-Pro）类似物被发现可作为二肽基肽酶IV（DPPIV）抑制剂，用于潜在治疗糖尿病和肥胖症。X射线晶体学数据表明，这些抑制剂与DPPIV的催化位点结合，氰基与DPPIV的丝氨酸残基形成共价键。C5取代基与该酶产生多种相互作用，并影响抑制剂的效力、化学稳定性、选择性和药代动力学性质。优化后的类似物具有极强的效力，其抑制常数（K(i)）低于纳摩尔级别，化学性质稳定，在血浆存在的情况下效力几乎不降低，并且对相关肽酶表现出超过1000倍的选择性。最佳化合物还具有良好的药代动力学性质，并且在ZDF大鼠的口服葡萄糖耐量试验中能够有效降低血糖。
