A high yielding and enantioselective synthesis of α-substituted hydroxamic acids as inhibitors of matrix metalloproteinases is described.

A series of novel matrix metalloproteinase inhibitors is described in which selectivity between MMP and 'sheddase' activity has been achieved and which demonstrate potent in vivo activity in models of arthritis and cancer.

An efficient solution phase synthesis of substituted benzimidazol-2-ones is described. Polymer-supported thiophenol is used to remove excess alkylating agents. A library of 24 mono- and di-substituted benzimidazol-2-ones has been prepared in 60–99% yield and 65–99% purity.

A series of N-alpha-mercaptoacetyl containing dipeptides have been prepared on solid-phase supports as putative matrix metalloprotease (MMP) inhibitors. Inhibitor design was based on a positional scanning approach of the amino acids present within a template molecule, previously shown to be an MMP inhibitor with good pharmacological characteristics. This study is the first step in a unique programme, designed to expand the repertoire of molecular templates which can be chosen as starting points for the development of more focused parallel and/or combinatorial libraries of MMP inhibitors as a means to accelerate the lead discovery process. This paper reports the success of such an approach in the development of agents with activity against a number of pathologically important MMPs. After screening of these positional scanning libraries, we have obtained important SAR information, in particular, pharmacophores with the ability to impart selectivity for particular MMP species.

A novel fluoropyrazole ribonucleoside has been shown to have significant anti-influenza activity in vitro. The compound is compared and contrasted with the structurally-related compound ribavirin in attempts to identify factors having significant bearing on the mode of action of both compounds.

A novel arylsilane based linker has been prepared for the solid phase synthesis of small molecule combinatorial libraries. Efficient cleavage is achieved using TFA via anchimerically assisted protiodesilylation to yield aromatic products possessing no residual linker functionality. (C) 1998 Elsevier Science Ltd. All rights reserved.

MAdCAM-1 specifically binds the lymphocyte integrin alpha 4 beta 7 and participates in the homing of leukocytes to intestinal mucosal sites. The LDT sequence located on the CD loop of MAdCAM-1 is an important binding site for MAdCAM-1/alpha 4 beta 7 interactions. N-Terminus acylation of the LDT motif and modification of the C-terminus carboxamide with amines led to low micromolar MAdCAM-1 inhibitors.

The in vitro potency of orally-active mercaptoacyl matrix metalloproteinase inhibitors is increased by the introduction of appropriate substituents on the mercaptoacyl moiety.

The preparation of a novel series of matrix metalloproteinase inhibitors is described, based on the use of a mercaptoacyl zinc binding moiety. The compounds have been tested in a model of rheumatoid arthritis and show good oral activity.

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The first enantiospecific synthesis of 5,6-dihydroxy-2-(NN-di-n-propylamino)tetralin [5,6-(HO)2DPAT] is reported. Starting from D- or L-serine either enantiomer is readily available in high optical purity.