The first 40 years of soft anticholinergic agents

Retrometabolic drug design approaches (RMDD) combine quantitative structure-activity and structure-metabolism relations (QSAR and QSMR) to improve the therapeutic index (ratio of toxic and effective dose, TI = TD50/ED50), of newly designed drugs. Soft drug (SD) design approaches, a subclass of RMDD, have been successfully employed in the development of safer drugs. The combination of “soft analog” and “inactive metabolite” techniques in drug development was first exemplified by the highly successful and safe soft corticosteroid, Loteprednol Etabonate. Similar techniques have been used to design safe topically active anticholinergic drugs with much reduced side effects. The “soft analog” and some of the “inactive metabolite” approaches have led to improved antimuscarinic drug candidates, which all (n = 76) can be fit with a bilinear exponential equation of activity vs molecular descriptors. The “remote inactive metabolite” approach was the most successful, having resulted in the new and very safe drug Sofpironium Bromide, which received regulatory approval to treat hyperhidrosis, a debilitating idiopathic disease and an unmet need.