Discovery of Novel 2‑Carbamoyl Morpholine Derivatives as Highly Potent and Orally Active Direct Renin Inhibitors

The renin–angiotensin–aldosterone system
(RAAS) plays
a key role in the regulation of blood pressure. Renin, the first and
rate-limiting enzyme of the RAAS, is an attractive target for the
treatment of hypertension and cardiovascular/renal diseases. Therefore,
various direct renin inhibitors (DRIs) have been researched over recent
decades; however, most exhibited poor pharmacokinetics and oral bioavailability
due to the peptidomimetic or nonpeptidomimetic structures with a molecular
weight (MW) of >600, and only aliskiren is approved. This study
introduces
a novel class of DRIs comprised of a 2-carbamoyl morpholine scaffold.
These compounds have a nonpeptidomimetic structure and a MW of <500.
The representative compound 26 was highly potent despite
not occupying S1′–S2′ sites or the opened flap
region used by other DRIs and exerted a significant antihypertensive
efficacy via oral administration on double transgenic mice carrying
both the human angiotensinogen and the human renin genes.