title: Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases.
abstract: The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp(2) character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. chunjian.liu@bms.com
authors.forename: Chunjian
authors.initials: C
authors.lastname: Liu
authors.forename: James
authors.initials: J
authors.lastname: Lin
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Wrobleski
authors.forename: Shuqun
authors.initials: S
authors.lastname: Lin
authors.forename: John
authors.initials: J
authors.lastname: Hynes
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Alaric J
authors.initials: AJ
authors.lastname: Dyckman
authors.forename: Tianle
authors.initials: T
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Wityak
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gillooly
authors.forename: Sidney
authors.initials: S
authors.lastname: Pitt
authors.forename: Ding Ren
authors.initials: DR
authors.lastname: Shen
authors.forename: Rosemary F
authors.initials: RF
authors.lastname: Zhang
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.forename: Luisa
authors.initials: L
authors.lastname: Salter-Cid
authors.forename: David J
authors.initials: DJ
authors.lastname: Shuster
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.forename: Punit H
authors.initials: PH
authors.lastname: Marathe
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Doweyko
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: Susan E
authors.initials: SE
authors.lastname: Kiefer
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Kish
authors.forename: John A
authors.initials: JA
authors.lastname: Newitt
authors.forename: Murray
authors.initials: M
authors.lastname: McKinnon
authors.forename: John H
authors.initials: JH
authors.lastname: Dodd
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Gary L
authors.initials: GL
authors.lastname: Schieven
authors.forename: Katerina
authors.initials: K
authors.lastname: Leftheris
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001682:Biological Availability; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C552704:4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo(1,2-f)(1,2,4)triazine-6-carboxamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D011758:Pyrroles; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14