title: 5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase.
abstract: A novel class of 5-cyanopyrimidine-based inhibitors of p38alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (>50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38alpha.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, New Jersey 08543-4000, USA.
authors.forename: Chunjian
authors.initials: C
authors.lastname: Liu
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Wrobleski
authors.forename: James
authors.initials: J
authors.lastname: Lin
authors.forename: Gulzar
authors.initials: G
authors.lastname: Ahmed
authors.forename: Axel
authors.initials: A
authors.lastname: Metzger
authors.forename: John
authors.initials: J
authors.lastname: Wityak
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gillooly
authors.forename: David J
authors.initials: DJ
authors.lastname: Shuster
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
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: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Doweyko
authors.forename: David
authors.initials: D
authors.lastname: Diller
authors.forename: Ian
authors.initials: I
authors.lastname: Henderson
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: John H
authors.initials: JH
authors.lastname: Dodd
authors.forename: Gary L
authors.initials: GL
authors.lastname: Schieven
authors.forename: Katerina
authors.initials: K
authors.lastname: Leftheris
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C505555:3-(5-cyano-6-(cyclopentylamino)pyrimidin-4-ylamino)-N-(isoxazol-3-yl)-4-methylbenzamide; C505554:3-(5-cyano-6-(isopropylamino)pyrimidin-4-ylamino)-N-(isoxazol-3-yl)-4-methylbenzamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D008070:Lipopolysaccharides; D009570:Nitriles; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14