Development of Angiotensin II Receptor Blockers for Cardiovascular Diseases

Angiotensin II receptors play a pivotal role in the onset and progression of cardiovascular diseases. By modulating the activity of angiotensin II receptors, a wide range of cardiovascular diseases can be effectively prevented and treated. Ace Therapeutics is the reliable partner for advancing innovative cardiovascular therapeutics, delivering end-to-end drug-development services that expedite the discovery and optimization of next-generation angiotensin II receptor blockers (ARBs).

The Role of Angiotensin II Receptor in Cardiovascular Diseases

Angiotensin II exerts its deleterious cardiovascular actions almost exclusively via the angiotensin II type 1 (AT₁) receptor, triggering vasoconstriction, inflammation, oxidative stress, and cellular proliferation. The principal pathophysiologic links between AT₁-receptor activation and cardiovascular disease are summarized below.

• Hypertension: AT₁ receptor activation induces vasoconstriction and aldosterone release, leading to elevated blood pressure.
• Heart failure: AT₁ receptor activation drives myocardial hypertrophy, cardiac fibrosis, and adverse cardiac remodeling.
• Atherosclerosis: AT₁ receptor activation promotes inflammatory responses and oxidative stress, accelerating the progression of atherosclerosis.
• Myocardial infarction: AT₁ receptor activation exacerbates myocardial injury and adverse cardiac remodeling post-infarction.

Pharmacologic antagonism of the AT₁ receptor effectively attenuates these pathophysiologic processes, providing a rational and potent therapeutic strategy for cardiovascular diseases.

Fig. 1 Schematic diagram showing AT_1aR-dependent signaling activated by intraluminal pressure. (Chen YL, Sonkusare SK, 2022)

Discovery of Angiotensin II Receptor Blockers

• Small Molecule Angiotensin II Receptor Blockers
  We provide end-to-end services for the discovery and development of next-generation angiotensin II receptor blockers. Our expertise enables the identification of highly selective small molecule candidates.
• Angiotensin II-targeted RNA Therapeutics
  We can design siRNAs and ASOs targeting angiotensinogen (AGT) and validate their gene-silencing efficacy through in vitro assays and in vivo studies.

In Vitro Pharmacodynamic Studies

• Angiotensin II Receptor Binding Assay
  We quantify the affinity of compounds for the AT₁ receptor (Ki value) through radioligand binding assays, while simultaneously evaluating their selectivity for the AT₂ subtype.
• Calcium Ion Flow Measurements
  We utilize fluorescent dyes or electrophysiological techniques to evaluate the effects of drugs on calcium ion flow, providing insights into their mechanisms of action and therapeutic potential.

In Vivo Pharmacodynamic Studies

• Effects on Hypertension
  We use customized animal model, including various specialized hypertension models, to evaluate the antihypertensive effects of drugs and supporting in vivo research on innovative hypertension therapies.
• Effects on Heart Failure
  We offer a variety of experimental animal models of heart failure to assess the effects of drug candidates on cardiac function and remodeling.

Ace Therapeutics is a contract research organization that provides clients with cardiovascular disease research, drug development and preclinical research services. If you are interested in our services, please do not hesitate to contact us.

1. Chen, Y.L.; Sonkusare, S.K. Mechanosensitive Angiotensin II Receptor Signaling in Pressure-Induced Vasoconstriction. J Am Heart Assoc. 2022, 11(4): e024740.