title: p38 MAP kinase inhibitors. Part 6: 2-arylpyridazin-3-ones as templates for inhibitor design.
abstract: p38 inhibitors based on 3,4-dihydropyrido[4,3-d]pyrimidazin-2-one template were synthesized and their SAR explored. Benchmark compounds 30, 35, and 36 were found to be potent against the enzyme. Crystal structure of p38 in complex with 30 indicated a key pi-stacking interaction with the pendant tyrosine residue-35 in the glycine-rich loop.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. ravi_natarajan@merck.com
authors.forename: Swaminathan R
authors.initials: SR
authors.lastname: Natarajan
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Heller
authors.forename: Kiyean
authors.initials: K
authors.lastname: Nam
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Singh
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.forename: Sangita
authors.initials: S
authors.lastname: Patel
authors.forename: James E
authors.initials: JE
authors.lastname: Thompson
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Fitzgerald
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Keefe
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005998:Glycine / Q000737:chemistry; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D011724:Pyridazines; D014443:Tyrosine; D048051:p38 Mitogen-Activated Protein Kinases; D005998:Glycine