Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis.

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.

A series of benzodiazepine inhibitors of the MMPs and TACE has been developed. These compounds display an interesting selectivity profile and should be useful tools for exploring the biological relevance of such selectivity.

The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production.

A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, MMP-13, and TACE was prepared and evaluated. Selective inhibitors of MMP-9, MMP-13, and TACE were identified, including the potent, orally active MMP-13 inhibitor 4p.

A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, and MMP-13 was prepared and evaluated both in vitro and in vivo. The most potent compound, 6e, has in vivo activity in a rat sponge-wrapped cartilage model.

Anthranilic acid derivatives bearing basic amines were prepared and evaluated in vitro and in vivo as inhibitors of MMP-1, MMP-9, MMP-13, and TACE. Piperazine 4u has been identified as a potent, selective, orally active inhibitor of MMP-9 and MMP-13.

A novel series of matrix metalloproteinase (MMP) inhibitors is described. Incorporation of a terminal α-mercaptoketone or α-mercaptoalcohol in the zinc binding domain of a series of inhibitors led to compounds exhibiting low nanomolar activity against collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).

A series of succinyl based mercaptoketones and diastereomeric mercaptoalcohols were prepared and evaluated in vitro as inhibitors of the matrix metalloproteinases collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).

Matrix metalloproteinases (MMP) have been implicated in a variety of diseases in which the destruction of connective tissue is an important pathological event. These include osteo and rheumatoid arthritis, tumor metastasis and angiogenesis, and corneal ulceration. As a result, there has been a great deal of activity directed towards the design of MMP inhibitors as therapeutic agents for the treatment of these conditions. Progress in the field has now evolved to a degree where potent, low molecular weight, orally active inhibitors have been discovered and advanced to clinical trials. While a majority of inhibitors are dipeptide derivatives, a non-peptide, orally active inhibitor has recently been reported. Some success has also been achieved in the design of subtype selective MMP inhibitors. The elucidation of X-ray and 0NMR structures of several MMPs, and the ability to create homology models of others has provided an understanding of some of the structural requirements leading to potency and specificity. Herein is a review of recent advances in the biology and chemistry of MMPs and MMP inhibitors, including the association of MMPs with specific disease processes, structure activity relationships of MMP inhibitors and factors affecting enzyme specificity and their correlation with MMP structure.

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Three minor limonoid components, rubralins A-C, were isolated from the root of Trichilia rubra, whose structures were determined by extensive spectroscopic studies. They showed moderate inhibitory activity in a β2-integrin mediated cell adhesion assay.

In the course of screening natural products for antagonists of CD18-mediated cell adhesion, an extract with inhibitory activity was identified from the stem and leaves of Conobea scoparioides. Bioassay-guided fractionation led to a pure compound, identified by spectroscopy as cucurbitacin E [1]. Although many biological activities have been reported for the cucurbitacins, this is the first report of cell adhesion inhibition. Furthermore, closely related cucurbitacin analogues had different potencies, pointing to substructural features that are important for the activity.

A series of seco-limonoids, with uncommon hemi ortho ester A-rings, was isolated from the root of Trichilia rubra. Their structures were determined by extensive spectroscopic studies. The five new and two previously known compounds were all found to be potent inhibitors of LFA-1:ICAM-1 mediated cell adhesion.