Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
J Med Chem. 2017 Jan 26;60(2):681-694. doi: 10.1021/acs.jmedchem.6b01584. Epub 2017 Jan 17.
Our initial structure-activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound 25 as a potent and selective A adenosine receptor (AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery of potent and selective adenosine A receptor antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups at position 2 of the benzothiazole scaffold and endowed with better solubility and oral bioavailability. Compounds 41 and 49 demonstrated a number of positive attributes with respect to in vitro ADME properties. Both compounds displayed good pharmacokinetic properties with 63% and 61% oral bioavailability, respectively, in rat. Further, compound 49 displayed oral efficacy in 6-OHDA lesioned rat model of Parkinson diseases.
我们最初对 7-甲氧基-4-吗啉基苯并噻唑衍生物的结构-活性关系进行了研究，这些衍生物在 2 位具有芳氧基-2-甲基丙酰胺部分，其中化合物 25 被鉴定为一种有效的、选择性的 A 腺苷受体（AAdoR）拮抗剂，具有合理的 ADME 和药代动力学性质。然而，较差的内在溶解度和低到中等的口服生物利用度使得该系列化合物不适合进一步开发。进一步使用基于结构的药物设计方法进行优化，发现了具有取代的 1-甲基环己基-羧酸酰胺基团的、在苯并噻唑骨架 2 位的、具有更好的溶解度和口服生物利用度的有效和选择性的腺苷 A 受体拮抗剂。化合物 41 和 49 在体外 ADME 性质方面表现出许多积极的特征。这两种化合物均显示出良好的药代动力学性质，在大鼠中的口服生物利用度分别为 63%和 61%。此外，化合物 49 在 6-OHDA 致帕金森病大鼠模型中显示出口服疗效。
