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Design and synthesis of potent,orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase |
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| Authors: | Stelmach John E Liu Luping Patel Sangita B Pivnichny James V Scapin Giovanna Singh Suresh Hop Cornelis E C A Wang Zhen Strauss John R Cameron Patricia M Nichols Elizabeth A O'Keefe Stephen J O'Neill Edward A Schmatz Dennis M Schwartz Cheryl D Thompson Chris M Zaller Dennis M Doherty James B |
| Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. john_stelmach@merck.com |
| Abstract: | The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38alpha inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of 15i which gave excellent suppression of TNF-alpha production in LPS-stimulated whole blood (IC(50)=10nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h). |
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