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, M.search; Hurley, C.A.search; Ward, S.I.search; Bergeron, P.search; Barrett, K.search; Balazs, M.search; Blair, W.S.search; Bull, R.search; Chakravarty, P.search; Chang, C.search; Crackett, P.search; Deshmukh, G.search; Devoss, J.search; Dragovich, P.S.search; Eigenbrot, C.search; Ellwood, C.search; Gaines, S.search; Ghilardi, N.search; Gibbons, P.search; Gradl, S.search; Gribling, P.search; Hamman, C.search; Harstad, E.search; Hewitt, P.search; Johnson, A.search; Johnson, T.search; Kenny, J.R.search; Koehler, M.F.search; Bir Kohli, P.search; Labadie, S.search; Lee, W.P.search; Liao, J.search; Liimatta, M.search; Mendonca, R.search; Narukulla, R.search; Pulk, R.search; Reeve, A.search; Savage, S.search; Shia, S.search; Steffek, M.search; Ubhayakar, S.search; van Abbema, A.search; Aliagas, I.search; Avitabile-Woo, B.search; Xiao, Y.search; Yang, J.search; Kulagowski, J.J.search
Journal J.MED.CHEM.search 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
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