Silanediol Inhibitors of Angiotensin-Converting Enzyme. Synthesis and Evaluation of Four Diastereomers of Phe[Si]Ala Dipeptide Analogues1

Abstract

Four stereoisomers of a Phe-Ala silanediol dipeptide mimic have been evaluated as inhibitors of angiotensin-converting enzyme (ACE) and compared to ketone-based inhibitors reported by Almquist et al. One stereogenic center of the isomers was derived from the individual enantiomers of methyl 3-hydroxy-2-methylpropionate, with separation of diastereomers after introduction of the second stereogenic center. The diastereomeric identities were established by X-ray crystallography of an intermediate. Inhibition of ACE by three of the silanediol diastereomers (IC₅₀ = 3.8−207 nM) closely paralleled that of the corresponding diastereomeric ketones (IC₅₀ = 1.0−46 nM). The fourth diastereomer, corresponding to the least inhibitory ketone (IC₅₀ = 3200 nM), exhibited an unexpected level of inhibition in the silanediol (IC₅₀ = 72 nM), suggesting an alternative mode of binding to the enzyme.