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Inhibition of MMP-1 and MMP-13 with phosphinic acids that exploit binding in the S2 pocket
L A Reiter1, J P Rizzi, J Pandit
1Pfizer Inc, Central Research Division, Groton, CT 06340, USA.
Abstract:
Through the use of empirical and computational methods, phosphinate-based inhibitors of MMP-1 and MMP-13 that bind into the S2 pocket of these enzymes were designed. The synthesis and testing of 2 suggested that binding was occurring as hypothesized. Structure determination of a co-crystal of 2 bound to the catalytic domain of MMP-1 confirmed the binding mode. Substituents binding into S2, S1', S2' and S3', were optimized yielding compounds with low double-digit nM IC50's against these enzymes.
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