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The development of monocyclic pyrazolone based cytokine synthesis inhibitors |
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| Authors: | Golebiowski Adam Townes Jennifer A Laufersweiler Matthew J Brugel Todd A Clark Michael P Clark Cynthia M Djung Jane F Laughlin Steven K Sabat Mark P Bookland Roger G VanRens John C De Biswanath Hsieh Lily C Janusz Michael J Walter Richard L Webster Mark E Mekel Marlene J |
| Affiliation: | Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA. golebiowski.a@pg.com |
| Abstract: | 4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented. |
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