Synthesis and the structure-activity relationships of cyclohexene-constrained phyenethylamine as Dipeptidyl Peptidase IV inhibitor

MEDI 417

Xiaofeng Li, xiaofeng.li@abbott.com1, Zhonghua Pei2, Thomas W. von Geldern2, David J. Madar2, Kenton Longenecker3, Hong Yong2, Thomas H. Lubben2, Kent D. Stewart2, Stephen J. Ballaron2, Michael A. Stashko2, Amanda K. Mika2, David W. A. Beno2, Glenn A. Reinhart2, Anita J. Kempf-Grote2, Hing L. Sham2, and James M. Trevillyan2. (1) Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064, (2) Abbott Laboratories, (3) Structural Biology, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, 60064
Dipeptidyl peptidase (DPPIV) is a widely distributed serine protease which degrades active glucagon-like peptide-1 (GLP-1 (7-36)) to inactive GLP-1 (9-36). GLP-1 is a gut hormone that stimulates glucose-dependent insulin secretion and inhibits glucagon secretion. Blockade of GLP-1 degradation through inhibition of DPPIV improves glucose tolerance with minimal risk of hypoglycemia, and has become a potentially useful therapy for type II diabetes. We have identified a cyclohexene-constrained phenethylamine hit by high-throughput screening of human DPPIV. Extensive optimization of this lead led to a series of compounds that are highly potent against DPPIV, and selective against other closely related proteases. Optimization of physiochemical and pharmacokinetic properties eventually led to the identification of the development candidate ABT-341. In this poster, details of the synthesis, optimization and SAR of the cyclohexene-constrained phenethylamines will be described.
 

General Poster Session
7:00 PM-9:00 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006