Protease inhibitors - Part 12. Synthesis of potent matrix metalloproteinase and bacterial collagenase inhibitors incorporating sulfonylated N-4-nitrobenzyl-beta-alanine hydroxamate moieties

N-4-Nitrobenzyl-beta-alanine was reacted with alkyl/arylsulfonyl halides, f ollowed by conversion of the COOH to the CONHOH group. Structurally related compounds were obtained by reaction of N-4-nitrobenzyl-beta-alanine with a ryl isocyanates, arylsulfonyl isocyanates or benzoyl isothiocyanate, follow ed by similar conversion of the COOH into the CONHOH moiety. Another subser ies of derivatives was prepared from sulfanilyl- or metanilyl-4-nitrobenzyl -beta-alanine by reaction with arylsulfonyl isocyanates, followed by the in troduction of the hydroxamate moiety. The new compounds were assayed as inh ibitors of four matrix metalloproteinases (MMPs), MMP-1, MMP-2, MMP-8 and M MP-9, and of the Clostridium histolyticum collagenase (ChC). Some of the pr epared hydroxamate derivatives proved to be very effective collagenase/gela tinase inhibitors, depending on the substitution pattern at the sulfonamido moiety. Substitutions leading to the best inhibitors of MMP-1, a short-poc ket enzyme, were those involving pentafluorophenylsulfonyl or 3-trifluorome thyl-phenylsulfonyl at P-1' (K-I of 3-5 nM). For MMP-2, MMP-8 and MMP-9 (de ep-pocket enzymes), the best inhibitors were those containing perfluoroalky lsulfonyl- and substituted-arylsulfonyl moieties, such as pentafluorophenyl sulfonyl, 3- and 4-protected-aminophenylsulfonyl-, 3- and 4-carboxy-phenyls ulfonyl-, arylsulfonylureido- or arylsulfonylureido-sulfanilyl-/metanilyl m oieties at P-1'. Bulkier groups in this position, such as 1- and 2-naphthyl -, substituted-naphthyl or quinoline-8-yl- moieties, among others, led to l ess effective MMP/ChC inhibitors. The best ChC inhibitors were again those containing pentafluorophenylsulfonyl, 3- and 4-protected-aminophenylsulfony l P-1. groups. This study demonstrates that the 4-nitrobenzyl moiety, inves tigated here for the first time, is an efficient P-2' anchoring moiety, whe reas the beta-alanyl scaffold can successfully replace the alpha-amino acyl one, for obtaining potent MMP/ChC inhibitors. (C) 2000 Elsevier Science B. V. All rights reserved.