title: Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.
abstract: The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non-receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966.
authors.affiliation: Merck & Co., 33 Avenue Louis Pasteur, Boston, MA, United States. Electronic address: vladimir_simov@merck.com.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Simov
authors.affiliation: Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, MA, United States.
authors.forename: Sujal V
authors.initials: SV
authors.lastname: Deshmukh
authors.affiliation: FORMA Therapeutics, 500 Arsenal Street #100, Watertown, MA, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Dinsmore
authors.affiliation: Merck & Co., 33 Avenue Louis Pasteur, Boston, MA, United States.
authors.forename: Fiona
authors.initials: F
authors.lastname: Elwood
authors.affiliation: Merck & Co., 33 Avenue Louis Pasteur, Boston, MA, United States.
authors.forename: Rafael B
authors.initials: RB
authors.lastname: Fernandez
authors.affiliation: Merck & Co., 33 Avenue Louis Pasteur, Boston, MA, United States.
authors.forename: Yudith
authors.initials: Y
authors.lastname: Garcia
authors.affiliation: Merck & Co., 33 Avenue Louis Pasteur, Boston, MA, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Gibeau
authors.affiliation: Merck & Co., 33 Avenue Louis Pasteur, Boston, MA, United States.
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.affiliation: Ironwood Pharmaceuticals, 301 Binney Street, Cambridge, MA, United States.
authors.forename: Joon
authors.initials: J
authors.lastname: Jung
authors.affiliation: Merck & Co., 33 Avenue Louis Pasteur, Boston, MA, United States.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Katz
authors.affiliation: Alcon Laboratories, 6201 South Freeway, Fort Worth, TX, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Kraybill
authors.affiliation: Merck & Co., 33 Avenue Louis Pasteur, Boston, MA, United States.
authors.forename: Blair
authors.initials: B
authors.lastname: Lapointe
authors.affiliation: Merck & Co., 33 Avenue Louis Pasteur, Boston, MA, United States.
authors.forename: Sangita B
authors.initials: SB
authors.lastname: Patel
authors.affiliation: Merck & Co., 33 Avenue Louis Pasteur, Boston, MA, United States.
authors.forename: Tony
authors.initials: T
authors.lastname: Siu
authors.affiliation: Merck & Co., 33 Avenue Louis Pasteur, Boston, MA, United States.
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.affiliation: Celgene Corporation, 4550 Towne Centre Court, San Diego, CA, United States.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Young
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C507904:JAK1 protein, human; D053613:Janus Kinase 1
keywords: JAK1 kinase inhibitor; Janus Kinase; Structure-based design