| Identification | Back Directory | [Name]
BMS-986165 | [CAS]
1609392-27-9 | [Synonyms]
Tyk2-IN-4
BMS-986165
Deucravacitinib
Deucravacitinib(BMS986165)
Deucravacitinib (TYK2-IN-4
TYK2-IN-4;BMS986165;BMS-986165;BMS 986165
6-cyclopropaneamido-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}-N-(2H?)methylpyridazine-3-carboxamide
6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide | [Molecular Formula]
C20H22N8O3 | [MOL File]
1609392-27-9.mol | [Molecular Weight]
422.45 |
| Chemical Properties | Back Directory | [storage temp. ]
Store at -20°C | [solubility ]
DMF: 1 mg/ml; DMSO: 1 mg/ml; DMSO:PBS (pH 7.2) (1:2): 0.33 mg/ml | [form ]
A crystalline solid | [color ]
Off-white to light yellow |
| Questions And Answer | Back Directory | [Uses]
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. |
| Hazard Information | Back Directory | [Description]
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. | [General Description]
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.
| [Pharmacokinetics]
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 4?5 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).
| [Synthesis]
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. | [IC 50]
Tyk2 JH2: 0.2 nM (IC50); JAK1 JH2: 1 nM (IC50); IL-12; IL-23 |
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