Witiak D T, Hassan A M, Del Vecchio F R, Brumbaugh R J, Rahwan R G
J Med Chem. 1984 Sep;27(9):1215-9. doi: 10.1021/jm00375a023.
The PGF2 alpha antagonist 5,6-bis(benzyloxy)-1-oxo-2-propyl-2-indanpropionic acid (1) had previously been shown to provide significant protection against the abortifacient actions of PGF2 alpha in mice. To explore further structural concepts in drug design employed for the development of 1, several mono(benzyloxy) ketones (3-10) and alcohols (11-15) as well as a diacid (22) were prepared. None of these structural modifications resulted in compounds of greater superiority to 1 as uterine relaxants and 22 was void of any antagonistic properties, suggesting that the original rationale requiring one carboxyl group and two benzyloxy functions appropriately placed for maximum PGF2 alpha antagonism in this series was a good assumption. A carbonyl rather than hydroxyl group at position C-1 of the indan is most beneficial for reversible antagonism. Reduction of the ketone to the alcohol is of synthetic interest and discussed in some detail.
前列腺素F2α拮抗剂5,6 - 双（苄氧基）-1 - 氧代 - 2 - 丙基 - 2 - 茚丙酸（1）先前已被证明能对前列腺素F2α在小鼠中的堕胎作用提供显著保护。为了进一步探索用于开发化合物1的药物设计中的结构概念，制备了几种单（苄氧基）酮（3 - 10）和醇（11 - 15）以及一种二酸（22）。这些结构修饰均未产生比化合物1作为子宫松弛剂更具优势的化合物，并且化合物22没有任何拮抗特性，这表明在该系列中，为实现最大前列腺素F2α拮抗作用而需要一个羧基和两个适当位置的苄氧基官能团的原始理论是一个合理的假设。茚满C - 1位的羰基而非羟基对于可逆拮抗作用最为有利。将酮还原为醇具有合成意义，并进行了一些详细讨论。
