2. Academic Validation
  3. Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors

Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors

  • J Med Chem. 2013 Jun 13;56(11):4521-36. doi: 10.1021/jm400266t.
Jun Liang 1,  Anne van Abbema,  Mercedesz Balazs,  Kathy Barrett,  Leo Berezhkovsky,  Wade Blair,  Christine Chang,  Donnie Delarosa,  Jason DeVoss,  Jim Driscoll,  Charles Eigenbrot,  Nico Ghilardi,  Paul Gibbons,  Jason Halladay,  Adam Johnson,  Pawan Bir Kohli,  Yingjie Lai,  Yanzhou Liu,  Joseph Lyssikatos,  Priscilla Mantik,  Kapil Menghrajani,  Jeremy Murray,  Ivan Peng,  Amy Sambrone,  Steven Shia,  Young Shin,  Jan Smith,  Sue Sohn,  Vickie Tsui,  Mark Ultsch,  Lawren C Wu,  Yisong Xiao,  Wenqian Yang,  Judy Young,  Birong Zhang,  Bing-yan Zhu,  Steven Magnuson
Affiliations

Affiliation

  • 1 Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. liang.jun@gene.com
PMID: 23668484 DOI: 10.1021/jm400266t
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.

Figures
Products