Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
Bioorg Med Chem Lett. 2019 Aug 15;29(16):2320-2326. doi: 10.1016/j.bmcl.2019.06.018. Epub 2019 Jun 17.
The design, synthesis, and biological evaluation of novel 3-aryl-indazole derivatives as peripherally selective pan-Trk inhibitors are described. Three strategies were used to obtain a potent compound exhibiting low central nervous system (CNS) penetration and high plasma exposure: 1) a structure-based drug design (SBDD) approach was used to improve potency; 2) a substrate for an efflux transporter for lowering brain penetration was explored; and 3) the most basic pKa (pKa-MB) value was used as an indicator to identify compounds with good membrane permeability. This enabled the identification of the peripherally targeted 17c with the potency, kinase-selectivity, and plasma exposure required to demonstrate in vivo efficacy in a Complete Freund's adjuvant (CFA)-induced thermal hypersensitivity model.
描述了新型 3-芳基-吲唑衍生物作为外周选择性泛 Trk 抑制剂的设计、合成和生物评价。为了获得一种具有低中枢神经系统（CNS）穿透性和高血浆暴露的有效化合物，采用了三种策略：1）基于结构的药物设计（SBDD）方法用于提高效力；2）探索了用于降低脑穿透性的外排转运体的底物；3）最基本的 pKa（pKa-MB）值用作识别具有良好膜通透性的化合物的指标。这使得能够鉴定出具有效力、激酶选择性和血浆暴露的外周靶向 17c，从而在完全弗氏佐剂（CFA）诱导的热敏感性模型中证明体内疗效。
