Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2

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• 作者：Mark Zak ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4764-4785
• 全文大小：1055K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

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.