Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor

Renin is the rate-limiting enzyme in the renin–angiotensin–aldosterone
system (RAAS) which regulates blood pressure and renal function and
hence is an attractive target for the treatment of hypertension and
cardiovascular/renal diseases. However, the development of direct
renin inhibitors (DRIs) with favorable oral bioavailability has been
a longstanding challenge for many years. This problem was thought
to be because most of the reported DRIs were peptide-like structures
or nonpeptide-like structures with a molecular weight (MW) of >
600.
Therefore, we tried to find nonpeptidomimetic DRIs with a MW of <
500 and discovered the promising 2-carbamoyl morpholine derivative 4. In our efforts to improve the pharmacokinetic profile of 4 without a significant increase in the MW, we discovered
compound 18 (SPH3127), which demonstrated higher bioavailability
and a more potent antihypertensive effect in preclinical models than
aliskiren and has completed a phase II clinical trial for essential
hypertension.