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

Abstract

A search for structurally diversified Tyk2 JH2 ligands from <b>6</b> (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 <i>N</i>-methyl triazolyl moiety in <b>6</b>. The X-ray co-crystal structure of an early lead (<b>12</b>) 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 <b>29</b>. 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 <b>7</b> (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of <b>7</b>, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.