Optimization of triazole-based TGR5 agonists towards orally available agents†
Kentaro Futatsugi,Kevin B. Bahnck,Martin B. Brenner,Joanne Buxton,Janice E. Chin,Steven B. Coffey,Jeffrey Dubins,Declan Flynn,Denise Gautreau,Angel Guzman-Perez,John R. Hadcock,David Hepworth,Michael Herr,Terri Hinchey,Ann M. Janssen,Sandra M. Jennings,Wenhua Jiao,Sophie Y. Lavergne,Bryan Li,Mei Li,Michael J. Munchhof,Suvi T. M. Orr,David W. Piotrowski,Nicole S. Roush,Matthew Sammons,Benjamin D. Stevens,Gregory Storer,Jian Wang,Joseph S. Warmus,Liuqing Wei,Angela C. Wolford
Abstract
Reported herein is a medicinal chemistry effort towards the identification of orally available TGR5 agonist 12, which served as a dog tool compound for studies to increase confidence in this mechanism. With the challenge of striking the balance of TGR5 potency and desired clearance profile, the screening strategy as well as medicinal chemistry strategy are discussed in this article.
