Discovery of TD-0212, an Orally Active Dual Pharmacology AT₁ Antagonist and Neprilysin Inhibitor (ARNI).

ABSTRACT: Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy relative to ACE inhibitors but is associated with a higher risk of life-threatening angioedema due to bradykinin elevations. We hypothesized that dual AT₁ (angiotensin II type 1 receptor) blockade and NEP inhibition with a single molecule would produce similar antihypertensive efficacy to omapatrilat without the risk of angioedema since ACE (the rate limiting enzyme in bradykinin metabolism) would remain uninhibited. Merging the structures of losartan (an AT₁ antagonist) and thiorphan (a NEP inhibitor) led to the discovery of a novel series of orally active, dual AT₁ antagonist/NEP inhibitors (ARNIs) exemplifie

SUBMITTER: McKinnell RM 

PROVIDER: S-EPMC6331171 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature