具有增强膜通透性的新型JAK1选择性苯并咪唑抑制剂。
Novel JAK1-selective benzimidazole inhibitors with enhanced membrane permeability.
作者信息
Kim Hyungmi, Kim Mi Kyoung, Choo Hyunah, Chong Youhoon
机构信息
Department of Integrative Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
Center for Neuro-Medicine, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology, Yoseong-gu, Daejeon 305-350, Republic of Korea.
出版信息
Bioorg Med Chem Lett. 2016 Jul 15;26(14):3213-3215. doi: 10.1016/j.bmcl.2016.05.078. Epub 2016 May 27.
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=0.08-0.15μM; 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).
先前鉴定出的Janus激酶1（JAK1）选择性抑制剂1-(2-氨基乙基)-2-(哌啶-4-基)-1H-苯并[d]咪唑-5-甲酰胺（2），存在细胞通透性低的问题，这导致其药代动力学性质较差。在本研究中，通过在N(1)（羟烷基或甲氨基烷基）和C2（环己醇基）位置引入极性较小的氢键供体，制备了一系列新型苯并咪唑衍生物，这些衍生物表现出选择性JAK1抑制活性（对JAK1的IC50 = 0.08 - 0.15μM；JAK1选择性：相对于JAK2为26 - 40倍，相对于JAK3为12 - 23倍，相对于Tyk2为38 - 54倍），同时亲脂性显著增加（3.3 - 15.8倍）以及膜通透性提高（6.3 - 12倍）。
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