Martin Osterhout

p38 kinase inhibitors for the treatment of arthritis and osteoporosis: thienyl, furyl, and pyrrolyl ureas.

Inhibitors of the MAP kinase p38 are potentially useful for the treatment for osteoporosis, arthritis, and other inflammatory diseases. A series of thienyl, furyl, and pyrrolyl ureas has been identified as potent p38 inhibitors, displaying in vitro activity in the nanomolar range.

Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor.

Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).

Optimization of the 4-aryl group of 4-aryl-pyridine glucagon antagonists: development of an efficient, alternative synthesis

A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3- and 4-positions. However, substitution with a 2-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4-fluoro-2-hydroxy analogue 33, IC50=190 nM). For efficient preparation of 2-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.

Integration of optimized substituent patterns to produce highly potent 4-aryl-pyridine glucagon receptor antagonists

Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1R)-hydroxyethyl] and a 2-hydroxy group. Due to restricted rotation of the phenyl-pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC(50)=10-25 nM.