Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis |
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Authors: | Revesz Laszlo Blum Ernst Di Padova Franco E Buhl Thomas Feifel Roland Gram Hermann Hiestand Peter Manning Ute Rucklin Gerard |
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Institution: | Novartis Institutes for BioMedical Research, Arthritis & Bone Metabolism, CH-4002 Basel, Switzerland. laszlo.revesz@pharma.novartis.com |
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Abstract: | A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo1,2-b]pyridines was prepared and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha with high efficacy in the LPS induced TNFalpha release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.5 mg/kg p.o. |
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