Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors

被引：26

作者：

Corbett, J. W. ^{[1
]}

Dirico, K. ^{[1
]}

Song, W. ^{[1
]}

Boscoe, B. P. ^{[1
]}

Doran, S. D. ^{[1
]}

Boyer, D. ^{[1
]}

Qiu, X. ^{[1
]}

Ammirati, M. ^{[1
]}

VanVolkenburg, M. A. ^{[1
]}

McPherson, R. K. ^{[1
]}

Parker, J. C. ^{[1
]}

Cox, E. D. ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Groton, CT 06340 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 24期

关键词：

dipeptidyl peptidase IV; DPP-IV; diabetes;

D O I：

10.1016/j.bmcl.2007.10.063

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The cis-3-amino-4-(2-eyanopyrrolidide) -pyrrolidine template has been shown to afford low nanomolar inhibitors of human DPP-IV that exhibit a robust PK/PD profile. An X-ray co-crystal structure of 5 confirmed the proposed mode of binding. The potent single digit DPP-IV inhibitor 53 exhibited a preferred PK/PD profile in preclinical animal models and was selected for additional profiling. (c) 2007 Published by Elsevier Ltd.

引用

收藏

页码：6707 / 6713

页数：7

相关论文

共 11 条

[1]

Diaz Gilbert J., 2004, Journal of Pharmacological and Toxicological Methods, V50, P187, DOI 10.1016/j.vascn.2004.04.001

[2] Discovery of alogliptin: A potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV [J].

Feng, Jun ;

Zhang, Zhiyuan ;

Wallace, Michael B. ;

Stafford, Jeffrey A. ;

Kaldor, Stephen W. ;

Kassel, Daniel B. ;

Navre, Marc ;

Shi, Lihong ;

Skene, Robert J. ;

Asakawa, Tomoko ;

Takeuchi, Koji ;

Xu, Rongda ;

Webb, David R. ;

Gwaltney, Stephen L., II .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (10) :2297-2300

[3] SYNTHESIS AND CHARACTERIZATION OF LITHIUM AMINOBOROHYDRIDES - A NEW CLASS OF POWERFUL REDUCING AGENTS [J].

FISHER, GB ;

HARRISON, J ;

FULLER, JC ;

GORALSKI, CT ;

SINGARAM, B .

TETRAHEDRON LETTERS, 1992, 33 (32) :4533-4536

[4] Sitagliptin: Profile of a novel DPP-4 inhibitor for the treatment of type 2 diabetes [J].

Gallwitz, Baptist .

DRUGS OF TODAY, 2007, 43 (01) :13-25

[5] Synthesis of cyclic and acyclic β-amino acids via chelation-controlled 1,3-dipolar cycloaddition [J].

Hanselmann, R ;

Zhou, JC ;

Ma, P ;

Confalone, PN .

JOURNAL OF ORGANIC CHEMISTRY, 2003, 68 (22) :8739-8741

[6] Dipeptidyl peptidase-IV inhibitors: a major new class of oral antidiabetic drug [J].

Idris, Iskandar ;

Donnelly, Richard .

DIABETES OBESITY & METABOLISM, 2007, 9 (02) :153-165

[7] LITHIUM ALUMINUM-HYDRIDE ON SILICA-GEL - SELECTIVE REDUCTION OF KETONES AND CARBOXY ESTERS IN THE PRESENCE OF NITRO AND CYANO GROUPS [J].

KAMITORI, Y ;

HOJO, M ;

MASUDA, R ;

INOUE, T ;

IZUMI, T .

TETRAHEDRON LETTERS, 1983, 24 (25) :2575-2576

[8] Glucagon-like peptide-1: The basis of a new class of treatment for type 2 diabetes [J].

Knudsen, LB .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (17) :4128-4134

[9] Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog [J].

Rasmussen, HB ;

Branner, S ;

Wiberg, FC ;

Wagtmann, N .

NATURE STRUCTURAL BIOLOGY, 2003, 10 (01) :19-25

[10] Inhibitors of acyl-CoA:cholesterol O-acyltransferase.: 2.: Identification and structure-activity relationships of a novel series of N-alkyl-N-(heteroaryl-substituted benzyl)-N′-arylureas [J].

Tanaka, A ;

Terasawa, T ;

Hagihara, H ;

Sakuma, Y ;

Ishibe, N ;

Sawada, M ;

Takasugi, H ;

Tanaka, H .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (13) :2390-2410