2. Academic Validation
  3. 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

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.
Chunjian Liu 1,  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
Affiliations

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.

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