Discovery of potent and selective leukotriene A4 hydrolase inhibitors

MEDI 22

Cheryl A. Grice1, Frank U. Axe2, Scott D. Bembenek1, Christopher R. Butler1, Fawn Coles1, Paul J. Dunford1, James P. Edwards1, Anne M. Fourie1, Lars Karlsson1, Kathleen Lundeen1, Jason Riley1, Brad M. Savall1, Kevin Tays, ktays@prdus.jnj.com1, Jianmei Wei1, Kacy Williams1, and Xiaohua Xue1. (1) Johnson & Johnson Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, (2) Computer Aided Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121
The pro-inflammatory mediator leukotriene B4 (LTB4) is a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils and macrophages. Improper LTB4 regulation is thought to play a role in numerous inflammatory diseases. The generation of LTB4 in vivo is regulated by the action of leukotriene A4 hydrolase (LTA4H), a key enzyme in the arachidonic acid cascade, which stereospecifically catalyzes the transformation of the unstable epoxide, LTA4 to the diol LTB4. We wish to disclose our initial efforts to identify orally active inhibitors of LTA4H in an effort to advance a compound into Phase I clinical trials. This work focuses on the development of a series of benzoxazoles, benzthiazoles and benzimidazoles. The SAR, in vitro and in vivo activity as well as pharmacokinetic profiles of selected inhibitors will be discussed.
 

General Oral Session
1:30 PM-4:50 PM, Sunday, August 19, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007