Novel JAK1-selective benzimidazole inhibitors with enhanced membrane permeability

Abstract

The previously identified Janus kinase 1 (JAK1)-selective inhibitor, 1-(2-aminoethyl)-2-(piperidin-4-yl)-1H- benzo[d] imidazole-5-carboxamide (2), suffered from low cell permeability, which resulted in poor pharmacokinetic properties. In this study, by introducing less polar hydrogen bond donors at N-1 (a hydroxyalkyl or a methylaminoalkyl group) and C2 (a cyclohexanol group) positions, a series of novel benzimidazole derivatives were prepared, which exhibited selective JAK1 inhibitory activity (IC50 against JAK1 = 0.08-0.15 mu M; JAK1-selectivity = 26-40 fold vs JAK2, 12-23 fold vs JAK3, and 38-54 fold vs Tyk2) along with significantly increased lipophilicity (3.3-15.8 times) as well as membrane permeability (6.3-12 times). (C) 2016 Elsevier Ltd. All rights reserved.