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.
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.
Liu
Chunjian
C
Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. chunjian.liu@bms.com
Lin
James
J
Wrobleski
Stephen T
ST
Lin
Shuqun
S
Hynes
John
J
Wu
Hong
H
Dyckman
Alaric J
AJ
Li
Tianle
T
Wityak
John
J
Gillooly
Kathleen M
KM
Pitt
Sidney
S
Shen
Ding Ren
DR
Zhang
Rosemary F
RF
McIntyre
Kim W
KW
Salter-Cid
Luisa
L
Shuster
David J
DJ
Zhang
Hongjian
H
Marathe
Punit H
PH
Doweyko
Arthur M
AM
Sack
John S
JS
Kiefer
Susan E
SE
Kish
Kevin F
KF
Newitt
John A
JA
McKinnon
Murray
M
Dodd
John H
JH
Barrish
Joel C
JC
Schieven
Gary L
GL
Leftheris
Katerina
K
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
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