Inhibition of MMP-1 and MMP-13 with phosphinic acids that exploit binding in the S2 pocket.

Autor: Reiter LA; Pfizer Inc, Central Research Division, Groton, CT 06340, USA., 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
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 1999 Jan 18; Vol. 9 (2), pp. 127-32.
DOI: 10.1016/s0960-894x(98)00729-x
Abstrakt: 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.
Databáze: MEDLINE
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