Why the study?
Most direct renin inhibitors exhibit poor pharmacokinetics and oral bioavailability due to high molecular weight structures, leaving only aliskiren approved.
Does oral administration of novel 2-carbamoyl morpholine derivatives (compound 26) reduce blood pressure in double transgenic mice?
Does oral administration of novel 2-carbamoyl morpholine derivatives (compound 26) reduce blood pressure in double transgenic mice?
A novel class of direct renin inhibitors with a 2-carbamoyl morpholine scaffold and molecular weight <500 demonstrated significant oral antihypertensive efficacy in a transgenic mouse model.
Novel DRI data in animals warrant clinical caution; leaves open human translation and oral bioavailability gains.
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.
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Iijima et al. (2022) studied this question.
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