title: Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase.
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).
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. john_stelmach@merck.com
authors.forename: John E
authors.initials: JE
authors.lastname: Stelmach
authors.forename: Luping
authors.initials: L
authors.lastname: Liu
authors.forename: Sangita B
authors.initials: SB
authors.lastname: Patel
authors.forename: James V
authors.initials: JV
authors.lastname: Pivnichny
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.forename: Suresh
authors.initials: S
authors.lastname: Singh
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: John R
authors.initials: JR
authors.lastname: Strauss
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Cameron
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Nichols
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Keefe
authors.forename: Edward A
authors.initials: EA
authors.lastname: O'Neill
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Schmatz
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Schwartz
authors.forename: Chris M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Zaller
authors.forename: James B
authors.initials: JB
authors.lastname: Doherty
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases