Structure-based design of serine protease inhibitors: Discovery of selective chymase inhibitors containing a novel beta-amidophosphonic acid recognition motif

ORGN 623

M. J. Hawkins1, M. N. Greco1, E. T. Powell1, T. W. Corcoran2, L. De Garavilla1, J. A. Kauffman2, Y. Wang2, L. Minor2, N. Sukumar3, Z-W. Chen3, A. O. Pineda3, F. S. Matthews3, E. Di Cera, enrico@wust1.edu3, and Bruce E. Maryanoff4. (1) Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, PA 19477-0776, (2) Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Welsh and McKean Rds, PO Box 776, Spring House, PA 19477, (3) Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, (4) Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development
Human chymase, a chymotrypsin-like serine protease present in the mast cell and released on activation, has been implicated in various pathological conditions associated with inflammation, including airway inflammation. We identified ?-amidophosphonic acid 1 as a selective inhibitor of chymase (IC50 = 0.2 ?M) through routine screening. We solved the X-ray crystal structure of 2•chymase and used the information in a structure-based optimization protocol. Details of the interactions of 2 within the active site of chymase will be discussed. Compound 2 was efficacious in the standard sheep model of asthma. Further optimization of 2 led to a series of potent, selective, orally active chymase inhibitors, represented by 3, from which we identified a suitable compound for preclinical development. Details of these studies will be presented.

 

Technical Achievements in Organic Chemistry Awards
8:15 AM-12:00 PM, Wednesday, 13 September 2006 Moscone Center -- Room 135, Oral

Division of Organic Chemistry

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