Discovery of 1-amino-5H-pyrido[4,3-b]indol-4-carboxamide inhibitors of Janus kinase 2 (JAK2) for the treatment of myeloproliferative disorders.

Abstract

The JAK-STAT pathway mediates signaling by cytokines, which control survival, proliferation, and differentiation of a variety of cells. In recent years, a single point mutation (V617F) in the tyrosine kinase JAK2 was found to be present with a high incidence in myeloproliferative disorders (MPDs). This mutation led to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. The genetic, biological, and physiological evidence suggests that JAK2 inhibitors could be effective in treating MPDs. De novo design efforts of new scaffolds identified 1-amino-5H-pyrido[4,3-b]indol-4-carboxamides as a new viable lead series. Subsequent optimization of cell potency, metabolic stability, and off-target activities of the leads led to the discovery of 7-(2-aminopyrimidin-5-yl)-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (65). Compound 65 is a potent, orally active inhibitor of JAK2 with excellent selectivity, PK profile, and in vivo efficacy in animal models.

• Authors: Jongwon Lim, Brandon Taoka, Ryan D Otte, Kerrie Spencer, Christopher J Dinsmore, Michael D Altman, Grace Chan, Craig Rosenstein, Sujata Sharma, Hua-Poo Su, Alexander A Szewczak, Lin Xu, Hong Yin, Joan Zugay-Murphy, C Gary Marshall, Jonathan R Young
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 20 Pg. 7334-49 (Oct 27 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21942426 (Publication Type: Journal Article)

Chemical References

• 7-(2-aminopyrimidin-5-yl)-1-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-5H-pyrido(4,3-b)indole-4-carboxamide
• Carbolines
• Indoles
• Pyridines
• Pyrimidines
• Janus Kinase 2

Topics

• Administration, Oral
• Animals
• Carbolines (chemical synthesis, pharmacokinetics, pharmacology)
• Crystallography, X-Ray
• Dogs
• Haplorhini
• Hepatocytes (metabolism)
• Indoles (chemical synthesis, pharmacokinetics, pharmacology)
• Janus Kinase 2 (antagonists & inhibitors, metabolism)
• Mice
• Mice, Inbred C57BL
• Models, Molecular
• Molecular Structure
• Myeloproliferative Disorders (drug therapy)
• Phosphorylation
• Polycythemia Vera (drug therapy)
• Pyridines (chemical synthesis, pharmacokinetics, pharmacology)
• Pyrimidines (chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Stereoisomerism
• Structure-Activity Relationship