Design, synthesis, and anti-inflammatory properties of orally active 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38alpha mitogen-activated protein kinase inhibitors.
A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1- f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1- f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC 50 60 nM) and was active in a cell-based TNFalpha biosynthesis inhibition assay (IC 50 210 nM). Replacement of the C4 oxindole with 2-methyl-5- N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC 50 10 nM) and moderately improved functional inhibition in THP-1 cells. Further replacement of the C6 ester of the pyrrolo[2,1- f][1,2,4]triazine with amides afforded compounds with increased potency, excellent oral bioavailability, and robust efficacy in a murine model of acute inflammation (murine LPS-TNFalpha). In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies.
Hynes
John
J
Department of Immunology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. john.hynes@bms.com
Dyckman
Alaric J
AJ
Lin
Shuqun
S
Wrobleski
Stephen T
ST
Wu
Hong
H
Gillooly
Kathleen M
KM
Kanner
Steven B
SB
Lonial
Herinder
H
Loo
Derek
D
McIntyre
Kim W
KW
Pitt
Sidney
S
Shen
Ding Ren
DR
Shuster
David J
DJ
Yang
Xiaoxia
X
Zhang
Rosemary
R
Behnia
Kamelia
K
Zhang
Hongjian
H
Marathe
Punit H
PH
Doweyko
Arthur M
AM
Tokarski
John S
JS
Sack
John S
JS
Pokross
Matthew
M
Kiefer
Susan E
SE
Newitt
John A
JA
Barrish
Joel C
JC
Dodd
John
J
Schieven
Gary L
GL
Leftheris
Katerina
K
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / 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; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; C526796:N-cyclopentyl-4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo(2,1-f)(1,2,4)triazine-6-carboxamide; C526795:N-ethyl-4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo(2,1-f)(1,2,4)triazine-6-carboxamide; D011758:Pyrroles; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14