title: Synthesis and biological activity of quinolinone and dihydroquinolinone p38 MAP kinase inhibitors.
abstract: Synthesis and biological activities of some quinolinone and dihydroquinolinone p38 MAP kinase inhibitors are reported. Modifications to the dihydroquinolinone pharmacophore revealed that dihydroquinolinone may be replaced with a quinolinone pharmacophore and lead to enhanced p38 inhibitory activity. From a study of C-7 substitutions by amino acid side chains, a very potent series of compounds in the p38 enzyme assays was identified. Translation of the in vitro activity into reasonable whole blood activity can be improved in this series of compounds by judicious modification of the physical properties at appropriate regions of the lead.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. meng_hsin_chen@merck.com
authors.forename: Meng-Hsin
authors.initials: MH
authors.lastname: Chen
authors.forename: Patricia
authors.initials: P
authors.lastname: Fitzgerald
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Singh
authors.forename: Edward A
authors.initials: EA
authors.lastname: O'Neill
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Schwartz
authors.forename: Chris M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Keefe
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Zaller
authors.forename: James B
authors.initials: JB
authors.lastname: Doherty
mesh_terms: D018360:Crystallography, X-Ray; D003500:Cyclization; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D015363:Quinolones; D048051:p38 Mitogen-Activated Protein Kinases; C464966:VX-745