Potent and selective TYK2-JH1 inhibitors highly efficacious in rodent model of psoriasis

Development and Therapeutic Implications of Tyrosine Kinase 2 Inhibitors

“…Especially, it exhibited excellent selectivity over human ether-à-go-go-related gene (hERG, IC 50 > 30 μM) and over a panel of CYP450 enzymes (IC 50 s > 30 μM) . Following 3 mg/kg iv and 10 mg/kg po dosing, 40 was profiled in rat, dog, and mouse PK assays, which revealed moderate to good oral absorption with oral bioavailabilities of 32, 63, and >90%, respectively . Importantly, 40 significantly relieved disease progression and attenuated inflammation in IL-23 and imiquimod induced mouse psoriasis models …”

“…122 This medicinal chemistry campaign began with a virtual screening hit 37 (Figure 11), which showed moderate TYK2 potency (K i = 1000 nM), but poor selectivity over other JAK family members (<3-fold). 122 Initial optimization efforts toward 37 resulted in the lead compound 38 (Figure 11) containing the pyrrolidino-pyrimidine fused core as the hinge binding motif, which showed significantly improved TYK2 potency (K i = 1.8 nM) and ≥10-fold selectivity over JAKs 1−3. 122 Further, the pyrimidine in 38 was replaced by a pyridine ring, while the nitrogen was shifted from the pyrimidine to the A-ring, affording pyrrolidinopyridine analogues.…”

“…Based on an free energy-based approach to predict aqueous solubility, structural modifications, including the conversion of pyridine (the Aring) into a phenyl ring and the terminal hydrophilic group into tertiary amides, culminated in compound 40 (Figure 11), which showed remarkable improvement in kinetic solubility (pH 7.4) relative to compound 39 (270 μM for 40 vs 2.4 μM for 39), while retaining reasonable potency and selectivity. 122 40 also exhibited good overall solubility in fasted-simulated intestinal fluid (FaSSIF solubility = 240 μM) and simulated gastric fluid (SGF solubility = 2300 μM). 122 40 exhibited moderate to good selectivity over a panel of 10 relevant kinases and also good overall selectivity against a panel of 87 enzymes, receptors, and ion channels.…”

“…122 40 also exhibited good overall solubility in fasted-simulated intestinal fluid (FaSSIF solubility = 240 μM) and simulated gastric fluid (SGF solubility = 2300 μM). 122 40 exhibited moderate to good selectivity over a panel of 10 relevant kinases and also good overall selectivity against a panel of 87 enzymes, receptors, and ion channels. Especially, it exhibited excellent selectivity over human ether-a-go-go-related gene (hERG, IC 50 > 30 μM) and over a panel of CYP450 enzymes (IC 50 s > 30 μM).…”

“…122 Importantly, 40 significantly relieved disease progression and attenuated inflammation in IL-23 and imiquimod induced mouse psoriasis models. 122 4.1.4. Pyridones.…”