2. Academic Validation
  3. Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2

Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2

  • J Med Chem. 2013 Jun 13;56(11):4764-85. doi: 10.1021/jm4004895.
Mark Zak 1,  Christopher A Hurley,  Stuart I Ward,  Philippe Bergeron,  Kathy Barrett,  Mercedesz Balazs,  Wade S Blair,  Richard Bull,  Paroma Chakravarty,  Christine Chang,  Peter Crackett,  Gauri Deshmukh,  Jason DeVoss,  Peter S Dragovich,  Charles Eigenbrot,  Charles Ellwood,  Simon Gaines,  Nico Ghilardi,  Paul Gibbons,  Stefan Gradl,  Peter Gribling,  Chris Hamman,  Eric Harstad,  Peter Hewitt,  Adam Johnson,  Tony Johnson,  Jane R Kenny,  Michael F T Koehler,  Pawan Bir Kohli,  Sharada Labadie,  Wyne P Lee,  Jiangpeng Liao,  Marya Liimatta,  Rohan Mendonca,  Raman Narukulla,  Rebecca Pulk,  Austin Reeve,  Scott Savage,  Steven Shia,  Micah Steffek,  Savita Ubhayakar,  Anne van Abbema,  Ignacio Aliagas,  Barbara Avitabile-Woo,  Yisong Xiao,  Jing Yang,  Janusz J Kulagowski
Affiliations

Affiliation

  • 1 Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. mzak@gene.com
PMID: 23659214 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 analogue 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.

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