Soft drugs activated

A different task was pursued by the CM of CsA with various maleates 339 [ 148]. The CM demanded in this case the highly active Hoveyda catalyst D, that exhibits potency not reached by the phosphine-containing catalysts C and E. Under the conditions given in Scheme 65, metathesis with maleates 339 led (E)-selectively to the a,/J-unsaturated ester derivatives 340 in high yield. Compounds 340 still demonstrated activity comparable to that of CsA and are thus potential soft drugs via esterase-mediated biotransformation to the corresponding inactive carboxylic acids 341. 

P. Druzgala, G. Hochhaus, and N. Bodor, Soft drugs 10 Blanching activity and receptor binding affinity of a new type of glucocorticoid Ioteprednol etabonate, J. Steroid Biochem. 38 149 (1991). 

Synthesis of the soft drug , loteprednol etabonate, was achieved by starting with a known inactive metabolite of a known active dmg. The inactive metabolite was then modified to an active form which, after having achieved its therapeutic role, was subsequently metabolized to an inactive species. 

It is also important to distinguish prodrugs from soft drugs [17, 18] defined as biologically active compounds (drugs) characterized by a predictable and fast in vivo metabolism to inactive and nontoxic moieties, after they have achieved their therapeutic role. An example is afforded by the short-acting [5-blockcr esmolol, whose half-life of hydrolysis in human blood at pH 7.4 and 37 °C is 23 min [19]. 

Predictions of drug metabolism based on quantitative structure-metabolism relationships (QSMRs), expert systems, and molecular modeling of enzymatic sites The consequences of such reactions on activation and inactivation, toxification, and detoxification Prodrug and soft drug design Changes in physicochemical properties (pKa, lipophilicity, etc.) resulting from biotransformation... 

---