The “classical” renin angiotensin system (RAS) comprises Angiotensin Converting Enzyme (ACE), its peptide product Angiotensin II, and the peptide’s receptor, AT1. This system, which controls blood pressure, and fluid and electrolyte balance, was discovered in the first half of the 20th century. It has led to the creation of two large pharmaceutical franchises, the ACE inhibitors (ACEi) and the Angiotensin Receptor Blockers (ARBs). The first ACEi, Captopril was approved in 1980 and the first ARB, Losartan, in 1995. Besides the effects on blood pressure, increased Angiotensin II is associated with fibrosis, inflammation and vasoconstriction.
In the early 21st century, a parallel counter-regulatory pathway was discovered. This “alternative” RAS has a similar configuration including Angiotensin Converting Enzyme 2 (ACE2), its principal peptide product Angiotensin-(1-7), and two receptors for the peptide, Mas and MrgD.
Over the last twenty years, Constant Therapeutics and others have discovered that engagement of Angiotensin-(1-7) with Mas and MrgD leads to a number of clinically relevant biologic effects. Constant’s lead compound, TXA127, is a pharmaceutical formulation of Angiotensin-(1-7) and targets the Mas and MrdD receptors.