The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins. Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis. Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases. The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.

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Active Arginine Vasopressin Receptor Antagonists.-In continuation of developing vasopressin antagonists, the tricyclic pyrrolobenzodiazepine moiety in VPA-985 is replaced by the thienobenzazepine derivatives (IV) and (X). These ring systems are prepared by novel routes, the structure-activity relationship is described. Thienobenzazepines (XII) possess potent V 1a and V 2 receptor binding activity. Compound (XIIc) is a potent, orally active and highly selective V 2 antagonist. -(ARANAPAKAM, VENKATESAN; ALBRIGHT, J. DONALD; GROSU, GEORGE T.; CHAN, PETER S.; COUPET, JOSEPH; SAUNDERS, TRINA; RU, XUN; MAZANDARANI, H.; Bioorg. Med. Chem.