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

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.