title: p38 MAP kinase inhibitors. Part 3: SAR on 3,4-dihydropyrimido[4,5-d]pyrimidin-2-ones and 3,4-dihydropyrido[4,3-d]pyrimidin-2-ones.
abstract: p38 inhibitors based on 3,4-dihydropyrimido[4,5-d]pyrimidin-2-one and 3,4-dihydropyrido[4,3-d]pyrimidin-2-one platforms were synthesized and preliminary SAR explored. Among the pyrimido-pyrimidones the emergence of two sub-types of analogs-C7-amino-pyrimidines such as 24 and C7-amino-piperidines such as 42-characterized with good p38 inhibition and better off-target profiles in terms of ion channel activities was significant. Representative compound 54 in the pyrido-pyrimidone class was found to be equipotent with corresponding analog in the quinazolinone series.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. ravi_natarjan@merck.com
authors.forename: Swaminathan R
authors.initials: SR
authors.lastname: Natarajan
authors.forename: David D
authors.initials: DD
authors.lastname: Wisnoski
authors.forename: James E
authors.initials: JE
authors.lastname: Thompson
authors.forename: Edward A
authors.initials: EA
authors.lastname: O'Neill
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Keefe
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C507290:3,4-dihydropyridopyrimidin-2(1H)-one; D004791:Enzyme Inhibitors; D011724:Pyridazines; D011725:Pyridines; D011743:Pyrimidines; D011744:Pyrimidinones; D011799:Quinazolines; D048051:p38 Mitogen-Activated Protein Kinases; C464966:VX-745