Structure-activity relationship study of central pyridine-derived TYK2 JH2 inhibitors: Optimization of the PK profile through C4' and C6 variations

  • Bioorg Med Chem Lett. 2023 Jul 15;91:129373. doi: 10.1016/j.bmcl.2023.129373.
Zili Xiao  1 ,  Michael G Yang  2 ,  Chunjian Liu  2 ,  Trevor Sherwood  2 ,  John L Gilmore  2 ,  James Lin  2 ,  Peng Li  2 ,  Dauh-Rurng Wu  2 ,  John Tokarski  2 ,  Sha Li  2 ,  Lihong Cheng  2 ,  Chunshan Xie  2 ,  Jingsong Fan  2 ,  Elizabeth Dierks  2 ,  Joann Strnad  2 ,  Mary Ellen Cvijic  2 ,  Javed Khan  2 ,  Max Ruzanov  2 ,  Michael Galella  2 ,  Purnima Khandelwal  2 ,  Alaric J Dyckman  2 ,  Arvind Mathur  2 ,  Louis J Lombardo  2 ,  John E Macor  2 ,  Percy H Carter  2 ,  Nelly Aranibar  2 ,  James R Burke  2 ,  David S Weinstein  2
Affiliations
  • 1. Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States. Electronic address: [email protected].
  • 2. Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States.
PMID: 37315697 DOI: 10.1016/j.bmcl.2023.129373
Abstract

Efforts directed at improving potency and preparing structurally different Tyk2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2-4. The current SAR study resulted in the identification of 4h as a potent and selective Tyk2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described. The hWB IC50 of 4h was shown as 41 nM with 94% bioavailability in the mouse PK study.

Keywords
Autoimmune diseases; JAK; TYK2 JH2 inhibitor.
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