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Biotech / Medical : SCIO Scios Inc. -- Ignore unavailable to you. Want to Upgrade?

To: Biomaven who wrote (1462)	2/7/2003 4:59:07 PM
From: Biomaven	Respond to of 1477

Here's a description of the BI compound: p38 kinase inhibitors Peter R. Farina, Ph.D. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 p38 Mitogen-activated proteinase kinase (MAP kinase) plays a crucial role in regulating the production of several important pro-inflammatory cytokines (e.g. TNF- and IL-1 ). The enzyme responds to cellular stress due to osmotic changes, UV light, lipopolysaccharide (LPS) and certain cytokines. There are multiple forms of p38 kinase ( ? ? ? ) which are separately gene encoded. The function of these isoforms, however, is still largely undefined. Activation by phosphorylation is required for full functionality of the enzyme. A pivotal study by Lee and colleagues demonstrated that a class of pyridinylimidazoles could inhibit the kinase thereby blocking the production of TNF- from LPS stimulated macrophages. These findings indicated that blocking p38 MAP kinase could offer an attractive target for treating certain autoimmune diseases such as rheumatoid arthritis, IBD and psoriasis as well as other inflammatory diseases. Further efforts using X-ray crystallography supported earlier biochemical data that this class of inhibitors bound to the ATP pocket on the enzyme thereby offering tractable approaches to SAR. We report here the identification of a novel class of pyrazole ureas which are selective inhibitors of p38 MAP kinase. Structural analysis reveals that these compounds occupy a unique binding site on p38 kinase. Investigation of this series of compounds has led to potent inhibitors of TNF- release both in vitro and in vivo and ultimately to the selection of a clinical candidate (BIRB 796 BS). The results from a single escalating dose trial indicate that BIRB 796 BS is orally bioavailable, well tolerated and exhibits a good pharmacokinetic profile. A clinical study was also performed where LPS was administered intravenously to human subjects who received a single oral dose of BIRB 796 BS. Compared to placebo, the compound significantly inhibited systemic TNF- levels. These results corroborate pharmacodynamic effects observed in LPS challenged non-human primates. Therefore, p38 MAP kinase may provide a new therapeutic option in the treatment of immune and inflammatory based diseases Peter