The fact that carbon and silicone have similar, but also dissimilar, characteristics triggered the interest in substituting carbon with silanediol as a central, zinc chelating group. Silicone forms a dialkylsilanediol compound that is sufficiently hindered so the formation of a siloxane polymer does not occur. Silanediols are more stable than carbon diols so they are expected to have longer half-life. Silanediols are also neutral at physiological pH (do not ionize).
Four stereoisomers of Phe-Ala silanediol were compared to ketone-based inhibitors and the silanediol were found to be fourfold less potent than the ketone analogue. This is because silanediols are weaker zinc chelators compared with ketones. Replacement of the silanediol, with a methylsilano group gave little enzyme inhibition. This confirms that the silanediol group interacts with ACE as a transition state analogue and the interaction is in a manner similar to that of ketone. If the benzyl group of silanediol is replaced by an i-butyl group it gives a weaker ACE inhibitor. Introduction of a hydrophobic methyl phenyl gives a little more potency than an analogue with a tert-butyl-group at P. That suggests that methyl phenyl gives a better S1 recognition than a tert-butyl group.