Soft drugs. 21. Design and evaluation of soft analogs of propantheline

The soft drug approach was applied to synthesize seven soft analogs of propantheline, which by design display predictable and controllable decomposition to inactive metabolites. Their synthesis involved the quatemization of several different amine groups with the chloromethyl ester of 9-methylxanthene-9-carboxylic acid. The rates of disappearance were measured for all of the compounds and were found to be more rapid than that of propantheline bromide in a variety of chemical and biological media under in vitro conditions. One of the soft analogs was found to be equipotent with propantheline in an in vitro assay. This soft analog was found to be equipotent with propantheline, in vivo, in protecting the rats against indomethacin-induced gastric ulceration and in inducing mydriasis in rabbits on intravenous administration. The pupil sizes returned faster to predrug levels with the soft analog than with propantheline, indicating increased metabolic lability of the soft analog. The equipotency of this soft analog coupled with increased metabolic lability proves the rationality of the soft drug approach for the design of safer therapeutic agents with higher therapeutic indices.