Duncton Matthew A J, Murray Ryan B, Park Gary, Singh Rajinder
Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
Org Biomol Chem. 2016 Oct 4;14(39):9343-9347. doi: 10.1039/c6ob01646d.
Matched molecular pair analysis was used to evaluate the ability of a tetrazolone group to act as a bioisostere of a carboxylic acid. Compound 7, a tetrazolone of the anti-hypertensive drug, telmisartan 6, was shown to be a potent AT antagonist (K = 0.14 nM), with activity comparable to telmisartan itself (K = 0.44 nM). Additionally, compound 9, a tetrazolone congener of the marketed anti-cancer agent, bexarotene 8, was shown to be an agonist at the retinoid X receptor alpha (EC = 64 nM). Compounds containing a tetrazolone group showed similar microsomal stability and plasma protein binding to marketed acid counterparts, while also reducing the value for clog P. Furthermore, compound 7 displayed an improved rat pharmacokinetic profile cf. telmisartan 6. Taken together, the results demonstrate that a tetrazolone group may serve as a bioisostere for a carboxylic acid.
采用匹配分子对分析来评估四唑酮基团作为羧酸生物电子等排体的能力。抗高血压药物替米沙坦6的四唑酮化合物7被证明是一种有效的AT拮抗剂（K = 0.14 nM），其活性与替米沙坦本身相当（K = 0.44 nM）。此外，市售抗癌药贝沙罗汀8的四唑酮同系物化合物9被证明是视黄酸X受体α的激动剂（EC = 64 nM）。含有四唑酮基团的化合物显示出与市售酸类似物相似的微粒体稳定性和血浆蛋白结合能力，同时还降低了clog P值。此外，与替米沙坦6相比，化合物7显示出改善的大鼠药代动力学特征。综上所述，结果表明四唑酮基团可作为羧酸的生物电子等排体。
