Probing acid replacements of PTP1B inhibitors

MEDI 426

Steven J. Kirincich1, Bruce Follows, bfollows@wyeth.com1, Zhao-Kui Wan1, Douglas P. Wilson2, Junjun Wu, jjwu@wyeth.com2, Weixin Xu3, Diane Joseph-McCarthy, DJoseph@wyeth.com4, May Tam5, Dave Erbe6, Steve Tam2, James Tobin7, Yanling Zhang6, and Jinbo Lee1. (1) Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, (2) Chemical and Screening Sciences, Wyeth, 200 Cambridge Park Drive, Cambridge, MA 02140, (3) Structural Biology, Wyeth Research, Cambridge, MA 02140, (4) Department of Structural Biology & Computational Chemistry, Wyeth Research, Chemical & Screening Sciences, 200 Cambridge Park Drive, Cambridge, MA 02140, (5) Department of Cardiovascular and Metabolic Diseases, Wyeth, 200 CambridgePark Drive, Cambridge, MA 02140, (6) Cardiovascular and Metabolic Disease, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, (7) Cardiovascular & Metabolic Disease, Wyeth Research, 200 CambridgePark Drive, Cambridge, 02140
In an effort to replace the diacid of a PTP1B lead series with a monoacid, a number of acid mimetics were investigated which lead to the discovery of a novel PTP1B inhibitor. The initial hit exhibited competitive/reversible inhibition. The potency was further improved by 1000-fold using structure based drug design aided by molecular modeling. The X-ray structure of PTP1B in complex with our most potent monoacid revealed changes in the phosphate binding region needed to accommodate the tetrazole ring.
 

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