5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase.
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.
Liu
Chunjian
C
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, New Jersey 08543-4000, USA.
Wrobleski
Stephen T
ST
Lin
James
J
Ahmed
Gulzar
G
Metzger
Axel
A
Wityak
John
J
Gillooly
Kathleen M
KM
Shuster
David J
DJ
McIntyre
Kim W
KW
Pitt
Sidney
S
Shen
Ding Ren
DR
Zhang
Rosemary F
RF
Zhang
Hongjian
H
Doweyko
Arthur M
AM
Diller
David
D
Henderson
Ian
I
Barrish
Joel C
JC
Dodd
John H
JH
Schieven
Gary L
GL
Leftheris
Katerina
K
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
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