Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2

  • J Med Chem. 2021 Jan 14;64(1):677-694. doi: 10.1021/acs.jmedchem.0c01698.
Chunjian Liu  1 ,  James Lin  1 ,  Charles Langevine  1 ,  Daniel Smith  2 ,  Jianqing Li  2 ,  John S Tokarski  3 ,  Javed Khan  3 ,  Max Ruzanov  3 ,  Joann Strnad  4 ,  Adriana Zupa-Fernandez  4 ,  Lihong Cheng  4 ,  Kathleen M Gillooly  4 ,  David Shuster  4 ,  Yifan Zhang  4 ,  Anil Thankappan  4 ,  Kim W McIntyre  4 ,  Charu Chaudhry  5 ,  Paul A Elzinga  6 ,  Manoj Chiney  6 ,  Anjaneya Chimalakonda  6 ,  Louis J Lombardo  1 ,  John E Macor  1 ,  Percy H Carter  1 ,  James R Burke  4 ,  David S Weinstein  1
Affiliations
  • 1. Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 2. Department of Discovery Synthesis, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 3. Molecular Structure and Design, Molecular Discovery Technologies, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 4. Immunosciences Discovery Biology, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 5. Leads Discovery and Optimization, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 6. Metabolism and Pharmacokinetic Department, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
PMID: 33370104 DOI: 10.1021/acs.jmedchem.0c01698
Abstract

A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 Inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 Inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.

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