Synthesis and pharmacological evaluation of indanpropionic acids as uterine relaxants

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.