Soft drug esterases

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. 

In the case of remifentanil it was also proved that, as predicted by the basic principles used in soft drug design, the possibility of drug interactions could be minimized by building metabolic considerations into the structure. Clearance, volume of distribution, and terminal half-life data indicated that coadministration of esmolol has no significant (P < 0.05) effect on the pharmacokinetics (or pharmacodynamics) of remifentanil in rats, despite both drugs being metabolized by nonspecific esterases (99,100). 

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