spacer JAK2 kinase (JH1 domain) in complex with the inhibitor TRANS-4-[(8AS)-2-[(1R)-1-HYDROXYETHYL]IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(8AH)-YL]CYCLOHEXANECARBONITRILE
Primary citation
Title Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2.
Authors Zak,; Hurley,; Ward,; Bergeron,; Barrett,; Balazs,; Blair,; Bull,; Chakravarty,; Chang,; Crackett,; Deshmukh,; Devoss,; Dragovich,; Eigenbrot,; Ellwood,; Gaines,; Ghilardi,; Gibbons,; Gradl,; Gribling,; Hamman,; Harstad,; Hewitt,; Johnson,; Johnson,; Kenny,; Koehler,; Bir Kohli,; Labadie,; Lee,; Liao,; Liimatta,; Mendonca,; Narukulla,; Pulk,; Reeve,; Savage,; Shia,; Steffek,; Ubhayakar,; van Abbema,; Aliagas,; Avitabile-Woo,; Xiao,; Yang,; Kulagowski,
Journal vol:56, pag:4764-4785 (2013), Identifiers: PubMed ID (23659214)search DOI (10.1021/jm4004895)
Abstract Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analog in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms, and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.
MeSH terms
Other entries described in this publication 4ivb, 4ivc, 4ivd