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
  • 1. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. [email protected]
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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