FPL-66564

(R)-2-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(methylthio)propanoic acid (FPL 66564) is the first example of a new class of critical care agents, the Ultra Short-Acting Angiotensin Converting Enzyme Inhibitors (USACEI).The design of FPL 66564 is based on the inactive metabolite approach whereby an active species is rapidly enzymically degraded in vivo to less or inactive metabolites (cf. the β-Blocker Esmolol).Its use should allow a rapid onset of action, ready titration of dose and ready control of hemodynamic responses.The three aspects of the medicinal chem. design of an USACEI that were considered particularly important are potency of active agent and metabolites, duration of action and site of metabolismStructure-activity relations led from (S)-2-(3-mercapto-2-methyl-1-oxopropoxy)acetic acid which is weakly active (IC₅₀ = 123nM) and slowly hydrolyzed by human blood (T_1/2 = 53 mins) to the methylthiomethyl compound FPL 66564.FPL 66564 is a potent ACE inhibitor (IC₅₀ = 5.7nM vs captopril IC₅₀ = 2.7nM) and is rapidly hydrolyzed by whole human blood (T_1/2 = 14 mins).The cleavage products of FPL 66564, (S)-3-mercapto-2-methylpropanoic acid and (R)-2-hydroxy-3-(methylthio)propanoic acid, are both inactive as ACE inhibitors and, being small hydrophilic mols., should be cleared rapidly.