title: 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.
abstract: 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.
authors: Department of Immunology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. john.hynes@bms.com
authors: John
authors: J
authors: Hynes
authors: Alaric J
authors: AJ
authors: Dyckman
authors: Shuqun
authors: S
authors: Lin
authors: Stephen T
authors: ST
authors: Wrobleski
authors: Hong
authors: H
authors: Wu
authors: Kathleen M
authors: KM
authors: Gillooly
authors: Steven B
authors: SB
authors: Kanner
authors: Herinder
authors: H
authors: Lonial
authors: Derek
authors: D
authors: Loo
authors: Kim W
authors: KW
authors: McIntyre
authors: Sidney
authors: S
authors: Pitt
authors: Ding Ren
authors: DR
authors: Shen
authors: David J
authors: DJ
authors: Shuster
authors: Xiaoxia
authors: X
authors: Yang
authors: Rosemary
authors: R
authors: Zhang
authors: Kamelia
authors: K
authors: Behnia
authors: Hongjian
authors: H
authors: Zhang
authors: Punit H
authors: PH
authors: Marathe
authors: Arthur M
authors: AM
authors: Doweyko
authors: John S
authors: JS
authors: Tokarski
authors: John S
authors: JS
authors: Sack
authors: Matthew
authors: M
authors: Pokross
authors: Susan E
authors: SE
authors: Kiefer
authors: John A
authors: JA
authors: Newitt
authors: Joel C
authors: JC
authors: Barrish
authors: John
authors: J
authors: Dodd
authors: Gary L
authors: GL
authors: Schieven
authors: Katerina
authors: K
authors: Leftheris
mesh_terms: 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
chemical_list: 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