Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 67, Issue -, Pages 175-187Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.03.070
Keywords
Kinase inhibitor; Janus family kinase; Structure-activity relationship; Crystal structure; Hit to lead; Immunology
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Funding
- DOE Office of Biological and Environmental Research
- National Institute of General Medical Sciences (NIH) [P41GM103393]
- National Center for Research Resources [P41RR001209]
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A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine I as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity. (C) 2013 Elsevier Masson SAS. All rights reserved.
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