title: Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors.
abstract: A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
authors.affiliation: Department of Medicinal Chemistry, Argenta, 8/9 Spire Green Centre, Harlow CM19 5TR, United Kingdom. janusz.kulagowski@glpg
authors.forename: Janusz J
authors.initials: JJ
authors.lastname: Kulagowski
authors.forename: Wade
authors.initials: W
authors.lastname: Blair
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bull
authors.forename: Christine
authors.initials: C
authors.lastname: Chang
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.forename: Hazel J
authors.initials: HJ
authors.lastname: Dyke
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
authors.forename: Paul
authors.initials: P
authors.lastname: Gibbons
authors.forename: Trevor K
authors.initials: TK
authors.lastname: Harrison
authors.forename: Peter R
authors.initials: PR
authors.lastname: Hewitt
authors.forename: Marya
authors.initials: M
authors.lastname: Liimatta
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hurley
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.forename: Tony
authors.initials: T
authors.lastname: Johnson
authors.forename: Jane R
authors.initials: JR
authors.lastname: Kenny
authors.forename: Pawan
authors.initials: P
authors.lastname: Bir Kohli
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Maxey
authors.forename: Rohan
authors.initials: R
authors.lastname: Mendonca
authors.forename: Kyle
authors.initials: K
authors.lastname: Mortara
authors.forename: Jeremy
authors.initials: J
authors.lastname: Murray
authors.forename: Raman
authors.initials: R
authors.lastname: Narukulla
authors.forename: Steven
authors.initials: S
authors.lastname: Shia
authors.forename: Micah
authors.initials: M
authors.lastname: Steffek
authors.forename: Savita
authors.initials: S
authors.lastname: Ubhayakar
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.forename: Anne
authors.initials: A
authors.lastname: van Abbema
authors.forename: Stuart I
authors.initials: SI
authors.lastname: Ward
authors.forename: Bohdan
authors.initials: B
authors.lastname: Waszkowycz
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
mesh_terms: D000818:Animals; D002460:Cell Line; D007093:Imidazoles / Q000737:chemistry*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013379:Substrate Specificity
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C029899:imidazole; D053613:Janus Kinase 1; D053614:Janus Kinase 2