Recent advances in retrometabolic design approaches

The retrometabolic drug design approaches simultaneously incorporate struct ure activity (SAR) and structure metabolism (SMR) relationships in the desi gn process. Two major approaches were developed, the chemical delivery syst ems (CDS), which allow chemical-enzymatic targeting of drugs via strategic sequential enzymatic activation of the inactive CDSs. On the opposite end o f the retrometabolic design loop are the soft drugs (SD), which are designe d to have highly improved therapeutic indeces by controlling their metaboli sm, after they achieve their therapeutic role. One of the most successful S D class is the 'inactive metabolite approach', where the design starts from an inactive metabolite of a drug. Its strategic manipulation yields an iso steric/isoelectronic drug analog, which is enzymatically deactivated to the very inactive metabolite at the desired compartment and with controlled ra te. Overall, retrometabolic approaches represent a complex collection of ch emical-enzymatic means for the design of safer drugs and for their controll ed release. Most recent advances involve FDA approval of a soft steroid, as well as the first successful brain targeting of various neuropeptides and their brain-targeted analogs. (C) 1999 Elsevier Science B.V. All rights res erved.