Inhibition of MMP-1 and MMP-13 with phosphinic acids that exploit binding in the S-2 pocket

Authors
Reiter, LA Rizzi, JP Pandit, J Lasut, MJ McGahee, SM Parikh, VD Blake, JF Danley, DE Laird, ER Lopez-Anaya, A Lopresti-Morrow, LL Mansour, MN Martinelli, GJ Mitchell, PG Owens, BS Pauly, TA Reeves, LM Schulte, GK Yocum, SA
Citation
La. Reiter et al., Inhibition of MMP-1 and MMP-13 with phosphinic acids that exploit binding in the S-2 pocket, BIOORG MED, 9(2), 1999, pp. 127-132
Citations number
19
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
ISSN journal
0960894X → ACNP
Volume
9
Issue
2
Year of publication
1999
Pages
127 - 132
Database
ISI
SICI code
0960-894X(19990118)9:2<127:IOMAMW>2.0.ZU;2-1
Abstract
Through the use of empirical and computational methods, phosphinate-based i nhibitors of MMP-1 and MMP-13 that bind into the S-2 pocket of these enzyme s were designed. The synthesis and testing of 2 suggested that binding was occurring as hypothesized. Structure determination of a co-crystal of 2 bou nd to the catalytic domain of MMP-1 confirmed the binding mode. Substituent s binding into S-2, S-1', S-2' and S-3', were optimized yielding compounds with low double-digit nM IC50's against these enzymes. (C) 1999 Elsevier Sc ience Ltd. All rights reserved.