Angiotensin is a peptide hormone that causes blood vessels to constrict and blood pressure to increase. It is part of the renin-angiotensin system that regulates blood pressure. Among them, angiotensin I can be converted to angiotensin II by the removal of two C-terminal residues by an angiotensin-converting enzyme (ACE). Angiotensin II acts on the central nervous system to increase the production of vasopressin. Besides, it acts on venous and arterial smooth muscle to cause vasoconstriction. At the same time, it also increases aldosterone secretion, acting as an endocrine, autocrine/paracrine, and endocrine hormone.
Endothelin is a vasoconstrictor peptide composed of 21 amino acids that is mainly produced in endothelial cells and plays a key role in vascular homeostasis. Endothelin acts by activating two G protein-coupled receptors, the endothelin A and endothelin B receptors. Among them, endothelin A receptors are mainly located on vascular smooth muscle cells and mediate vasoconstriction. Endothelin A receptors are selective for endothelin 1, which contributes to vascular dysfunction associated with cardiovascular disease, especially atherosclerosis and hypertension.
Sparsentan (RE-021) is a dual angiotensin II and endothelin A receptor antagonist.
Sparsentan (RE-021) is a highly potent dual angiotensin II and endothelin A receptor antagonist with Ki values of 0.8 and 9.3 nM, respectively. Moreover, Sparsentan dose-dependently antagonizes the angiotensin II-induced pressor response with an ED50 value of 0.8 µmol/kg i.v. and 3.6 µmol/kg p.o. In addition, Sparsentan shows efficacious and long-acting in the big ET-1-induced pressor model. It causes a significant lowering of blood pressure at the lowest dose tested (10 µmol/kg/day) in spontaneously hypertensive rats. Besides, Sparsentan shows good oral bioavailability in rats, dogs, and monkeys, averaging 40%, 86%, and 21% F, respectively. Sparsentan at 100 µmol/kg/day essentially converts the spontaneously hypertensive rats into normotensive rats during the course of its pharmacokinetic duration.
In conclusion, Sparsentan (RE-021) is a highly selective dual antagonist of angiotensin II and endothelin A receptors and can be used in the study of hypertensive disorders, etc.
 Natesan Murugesan, et al. J Med Chem. 2005 Jan 13;48(1):171-9.
 M C Verhaar, et al. Circulation. 1998 Mar 3;97(8):752-6.