Menarini Ricerche, Rome, Italy.
J Med Chem. 2010 May 27;53(10):4148-65. doi: 10.1021/jm100176s.
As part of a project aimed at the identification of a series of small, orally available antagonists for the hNK(2) receptor, starting from one of our capped dipeptide libraries, we succeeded in the chemical optimization of the first identified leads, finally producing a class of molecules with significant activity in our animal model after iv administration. We herein report the results of further chemical modifications made to reduce the overall peptide character of this series and the consequent improvement of their in vivo antagonist activity. The present work identified 6-methylbenzo[b]thiophene-2-carboxylic acid (1-[(S)-1-benzyl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]butylcarbamoyl]cyclopentyl)amide (10i), endowed with subnanomolar potency in all the in vitro tests and being highly potent and of long duration upon in vivo testing after both iv and id dosing.
作为旨在鉴定一系列针对 hNK(2)受体的小的、可口服的拮抗剂的项目的一部分，我们从我们的一个封闭二肽文库开始，成功地对第一个鉴定出的先导化合物进行了化学优化，最终在我们的动物模型中产生了一类具有显著活性的化合物在 iv 给药后。本文报告了进一步进行化学修饰的结果，这些修饰旨在降低该系列化合物的整体肽性质，并因此提高其体内拮抗剂活性。本工作鉴定出 6-甲基苯并[b]噻吩-2-羧酸（1-[(S)-1-苄基-4-[4-(四氢吡喃-4-基甲基)哌嗪-1-基]丁基氨基甲酰基]环戊基）酰胺（10i），在所有体外试验中均具有亚纳摩尔效力，并且在 iv 和 id 给药后进行体内试验时具有高活性和长作用持续时间。
