In their first evaluation as inhibitors of an aspartic protease, silanediol peptidomimetics have been found to be nearly as potent as currently available pharmaceutical agents, in enzyme and cell protection assays. These neutral, cell-permeable transition state analogs therefore provide a novel foundation for the design of therapeutic agents.
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.
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