Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors

Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor 17 was a potent and isoform selective JNK3 inhibitor (IC50 = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome t(1/2) = 66 min and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds 17 and 27 in human JNK3 were solved at 1.84 A, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both hydrophobic pocket-I and hydrophobic pocket-II.

Automated summary

A potent and highly selective JNK3 inhibitor was developed from a thiophenyl-pyrazolourea scaffold, with good oral bioavailability and brain penetrant capability. The inhibitor showed significant inhibition to only JNK3, high stability in human liver microsome, and clean CYP-450 inhibition profile, making it a promising candidate for further development. The cocrystal structures of the inhibitor bound to the ATP pocket of human JNK3 indicated strong interactions in both hydrophobic pockets, providing insights into its mechanism of action.