Soft drugs. 12: Design, syntheses and evaluation of soft anticholinergics

Concepts involved in the design of soft drugs (drugs which, after achieving their therapeutic role, are metabolized in a predictable manner and at a controlled rate to non-toxic moieties) have been applied to methscopolamine (1). Selected aliphatic and cycloaliphatic esters (3) of a hypothetical carboxylic acid metabolite (2) of methscopolamine were designed and found to have anticholinergic activity. Six soft drug analogs of methscopolamine were tested for mydriatic activity in rabbit eye. At equieffective doses, the AUC24 hrs and the mydriatic recovery time were found to be significantly less with some of the soft drugs compared to methscopolamine and soft drug 3a was found to be shorter acting than tropicamide. At equieffective doses the AUC24 hrs for soft drugs ranged from 23.2% to 187% of that of methscopolamine. Significant dilation of the untreated eye was observed with scopolamine but not with the soft drugs after unilateral administration. Soft drug 3a exhibited only 2.3% of the AUC6 hrs (untreated eye) of that of methscopolamine.