Structure Report for: 2G5T

Longenecker, K.L., Fry, E.H., Lake, M.R., Solomon, L.R., Pei, Z., Li, X.

Title: Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors
Pei Z, Li X, Longenecker K, von Geldern TW, Wiedeman PE, Lubben TH, Zinker BA, Stewart K, Ballaron SJ and Trevillyan JM <16 more author(s)> Pei Z, Li X, Longenecker K, von Geldern TW, Wiedeman PE, Lubben TH, Zinker BA, Stewart K, Ballaron SJ, Stashko MA, Mika AK, Beno DW, Long M, Wells H, Kempf-Grote AJ, Madar DJ, McDermott TS, Bhagavatula L, Fickes MG, Pireh D, Solomon LR, Lake MR, Edalji R, Fry EH, Sham HL, Trevillyan JM (- 16)
Ref: Journal of Medicinal Chemistry, 49:3520, 2006 : PubMed
Abstract


ESTHER: Pei_2006_J.Med.Chem_49_3520
PubMedSearch: Pei 2006 J.Med.Chem 49 3520
PubMedID: 16759095
Gene_locus related to this paper: human-DPP4
Inhibitor(s) related to this paper: AAF, ACF, ADF

Abstract

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.