1. Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors
- Author
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Sue Sohn, Nico Ghilardi, Priscilla Mantik, Christine Chang, Mercedesz Balazs, Paul Gibbons, Jan Smith, Ivan Peng, Jason DeVoss, Bing-Yan Zhu, Kathy Barrett, Wade S. Blair, Yisong Xiao, Steven Shia, Birong Zhang, Jim Driscoll, Donnie Delarosa, Young G. Shin, Jeremy Murray, Steven Magnuson, Leo Berezhkovsky, Wenqian Yang, Anne van Abbema, Charles Eigenbrot, Lawren C. Wu, Adam R. Johnson, Pawan Bir Kohli, Vickie Tsui, Mark Ultsch, Jason Halladay, Amy Sambrone, Yingjie Lai, Joseph P. Lyssikatos, Yanzhou Liu, Kapil Menghrajani, Jun Liang, and Judy Young
- Subjects
Models, Molecular ,Administration, Oral ,Aminopyridines ,Biological Availability ,Pharmacology ,Crystallography, X-Ray ,Interferon-gamma ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Animals ,Structure–activity relationship ,Potency ,4-Aminopyridine ,Benzamide ,Cell potency ,TYK2 Kinase ,chemistry.chemical_classification ,Gene knockdown ,Chemistry ,Janus Kinase 3 ,Stereoisomerism ,Janus Kinase 1 ,Janus Kinase 2 ,STAT4 Transcription Factor ,Interleukin-12 ,Rats ,Enzyme ,Biochemistry ,Tyrosine kinase 2 ,Benzamides ,Microsomes, Liver ,Molecular Medicine ,Protein Binding - Abstract
Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
- Published
- 2013
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