BMS-986165 is a novel oral selective TYK2 inhibitor with a unique mechanism of action that is expected to provide a promising oral option to help patients effectively manage their psoriasis.
Deucravacitinib (trade name Sotykto) is a first-in-class tyrosine kinase 2 (TYK2) inhibitor recently approved for the treatment of moderate to severe plaque psoriasis. Psoriasis is a chronic inflammatory skin disease characterized by the formation of red patches and scaling on the skin. Discovered by Bristol Myers Squibb (BMS), deuterated colestitinib, also known as BMS-986165, is the first JAK inhibitor containing deuterium and the first approved selective TYK2 inhibitor, showing more than 50,000-fold selectivity over JAK1, JAK2 and JAK3.
Deucravacitinib is a tyrosine kinase 2 inhibitor which can be useful in the treatment of systemic lupus erythematosus.
Deucravacitinib, a highly selective allosteric TYK2 inhibitor, received its first approval from the FDA in 2022 for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy protein and lipid kinases and pseudokinases with the exception of BMPR2 (IC50 = 193 nM) and JAK1 JH2 pseudokinase domain (IC50 = 1 nM). Despite its potent affinity for JAK1 JH2, deucravacitinib elicited low functional activity in a JAK1/JAK3-dependent IL-2 stimulated cellular assay. BMS-986202 displays >10,000-fold selectivity for TYK2 JH2 over a diverse panel of 273 kinases and pseudokinases that include JAK family members. Like deucravacitinib, its high binding affinity to JAK1 JH2 (IC50 = 7.8 nM) did not translate to functional activity in the cellular assay.
The crystalline free base form of deucravacitinib exhibited poor aqueous solubility (5.2 μg/mL), which was still acceptable for preclinical studies. It showed moderate half-lives of 45 h across species (mouse, dog, and monkey). Excellent exposures and high bioavailability (F > 85%) in mice, dogs, and monkeys were obtained from oral pharmacokinetic studies at a 10 mpk dose. Following oral administration of deucravacitinib, the major metabolite in human plasma was the cyclopropyl carboxamide hydrolytic cleavage product 4 (6-amino-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide).
Lewis acid-mediated SNAr reaction of pyridazine 15.12 and aniline 15.7 gave 15.13 in 95% yield with excellent regioselectivity (∼185:1 15.13:15.14). Although an unconventional compound, 15.13 was isolated as a Zn-dicarboxylate due to its good solubility, ease of crystallization and isolation. The aryl pyridazine 15.13 then formed a C-N bond with amide 15.15 under Pd catalysis to afford the penultimate carboxylate 15.16 in 94% yield. Trideuterated methylamides were generated under standard amide coupling conditions. Deucravacitinib was prepared in 75% yield by crystallization in NMP and i-PrOH.
Tyk2 JH2: 0.2 nM (IC50); JAK1 JH2: 1 nM (IC50); IL-12; IL-23
