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

Chunjian Liu; James Lin; Stephen T Wrobleski; Shuqun Lin; John Hynes; Hong Wu; Alaric J Dyckman; Tianle Li; John Wityak; Kathleen M Gillooly; Sidney Pitt; Ding Ren Shen; Rosemary F Zhang; Kim W McIntyre; Luisa Salter-Cid; David J Shuster; Hongjian Zhang; Punit H Marathe; Arthur M Doweyko; John S Sack; Susan E Kiefer; Kevin F Kish; John A Newitt; Murray McKinnon; John H Dodd; Joel C Barrish; Gary L Schieven; Katerina Leftheris

doi:10.1021/jm100540x

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

J Med Chem. 2010 Sep 23;53(18):6629-39. doi: 10.1021/jm100540x.

Affiliation

¹ Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. chunjian.liu@bms.com

PMID: 20804198
DOI: 10.1021/jm100540x

Abstract

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.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Arthritis, Experimental / drug therapy
Arthritis, Rheumatoid / drug therapy
Biological Availability
Caco-2 Cells
Crystallography, X-Ray
Female
Humans
Hydrogen Bonding
In Vitro Techniques
Inflammation / drug therapy
Inflammation / metabolism
Lipopolysaccharides / pharmacology
Male
Mice
Mice, Inbred BALB C
Microsomes, Liver / metabolism
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 14 / chemistry
Models, Molecular
Molecular Conformation
Protein Binding
Pyrroles / chemical synthesis*
Pyrroles / pharmacokinetics
Pyrroles / pharmacology
Rats
Rats, Inbred Lew
Rats, Sprague-Dawley
Stereoisomerism
Structure-Activity Relationship
Triazines / chemical synthesis*
Triazines / pharmacokinetics
Triazines / pharmacology
Tumor Necrosis Factor-alpha / biosynthesis

Substances

4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo(1,2-f)(1,2,4)triazine-6-carboxamide
Anti-Inflammatory Agents, Non-Steroidal
Lipopolysaccharides
Pyrroles
Triazines
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinase 14

Associated data

PDB/3MVL