title: 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.affiliation: Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States. jongwon_lim@merck.com
authors.forename: Jongwon
authors.initials: J
authors.lastname: Lim
authors.forename: Brandon
authors.initials: B
authors.lastname: Taoka
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Otte
authors.forename: Kerrie
authors.initials: K
authors.lastname: Spencer
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Dinsmore
authors.forename: Michael D
authors.initials: MD
authors.lastname: Altman
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.forename: Craig
authors.initials: C
authors.lastname: Rosenstein
authors.forename: Sujata
authors.initials: S
authors.lastname: Sharma
authors.forename: Hua-Poo
authors.initials: HP
authors.lastname: Su
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.forename: Joan
authors.initials: J
authors.lastname: Zugay-Murphy
authors.forename: C Gary
authors.initials: CG
authors.lastname: Marshall
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Young
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002243:Carbolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D009196:Myeloproliferative Disorders / Q000188:drug therapy*; D010766:Phosphorylation; D011087:Polycythemia Vera / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C568962:7-(2-aminopyrimidin-5-yl)-1-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-5H-pyrido(4,3-b)indole-4-carboxamide; D002243:Carbolines; D007211:Indoles; D011725:Pyridines; D011743:Pyrimidines; D053614:Janus Kinase 2