Probing the Requirements for Dual Angiotensin-Converting Enzyme C‑Domain Selective/Neprilysin Inhibition

Selective inhibition of the angiotensin-converting
enzyme C-domain
(cACE) and neprilysin (NEP), leaving the ACE N-domain (nACE) free
to degrade bradykinin and other peptides, has the potential to provide
the potent antihypertensive and cardioprotective benefits observed
for nonselective dual ACE/NEP inhibitors, such as omapatrilat, without
the increased risk of adverse effects. We have synthesized three 1-carboxy-3-phenylpropyl
dipeptide inhibitors with nanomolar potency based on the previously
reported C-domain selective ACE inhibitor lisinopril-tryptophan (LisW)
to probe the structural requirements for potent dual cACE/NEP inhibition.
Here we report the synthesis, enzyme kinetic data, and high-resolution
crystal structures of these inhibitors bound to nACE and cACE, providing
valuable insight into the factors driving potency and selectivity.
Overall, these results highlight the importance of the interplay between
the S1′ and S2′ subsites for ACE
domain selectivity, providing guidance for future chemistry efforts
toward the development of dual cACE/NEP inhibitors.