Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2013-06, Vol.56 (11), p.4764-4785

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.