Research Progress on the Mechanism of Hypertension and New Drug Development

October 8th of every year is National Hypertension Day. Hypertension is a cardiovascular syndrome with elevated arterial pressure as its main clinical manifestation, which can damage vital organs, leading to damage to target organs such as stroke, coronary artery disease, heart failure, and chronic kidney failure. The occurrence and development of hypertension are related to multiple factors, including hyperactivity of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system (RAAS), renal excretion dysfunction, vascular endothelial damage, insulin resistance, and genetic factors. At present, the main treatment for hypertension remains pharmacological therapy. The antihypertensive drugs currently available on the market mainly include six categories: calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNI), thiazide diuretics, and beta-blockers.

The mechanism of hypertension serves as the theoretical basis for the development of new antihypertensive drugs. Currently, the research and development of new drugs are mostly focused on new mechanisms or new targets. Dual-channel blocking CCBs, direct renin inhibitors, ETA/ETB dual endothelin receptor antagonists, AT1 inhibitors, APA inhibitors, sodium-potassium ion channel converter inhibitors, natriuretic peptide receptor agonists, DβH inhibitors, and sGC stimulants are all potential directions for the future development of new antihypertensive drugs.

1. Dual-channel Blocking CCBs

CCBs are one of the commonly used antihypertensive drugs in clinical practice, mainly dihydropyridines (DHP CCBs), which selectively act on voltage-dependent L-type Ca2+ channels. Commonly used drugs include nifedipine and amlodipine. However, CCBs can cause adverse reactions such as peripheral edema, facial flushing, and tachycardia, which can easily lead to poor patient compliance and failure to effectively control blood pressure. Current studies have confirmed that novel DHP CCBs such as efonidipine, benidipine, and nilvadipine can partially block both L-type and T-type calcium channels. Randomized clinical trials have found that compared with drugs that only act on L-type Ca2+ channels, efonidipine and benidipine have similar blocking effects on L-type calcium channels, while the probability of peripheral edema and reflex tachycardia is lower. Therefore, compared to L-type calcium channel blockers, dual blocking of L- and T-type calcium channels may have better therapeutic effects on hypertension, providing better protection for the cardiovascular and kidney systems, and reducing the occurrence of adverse reactions such as peripheral edema.

2.Direct Renin Inhibitors

RAAS plays a crucial role in the development of hypertension. Renin, secreted by juxtaglomerular cells, converts angiotensinogen synthesized in the liver into angiotensin I (Ang I), which is then converted into angiotensin II (Ang II) under the activation of angiotensin-converting enzyme (ACE). Ang II primarily acts on the angiotensin receptor subtype 1 (AT1), promoting vasoconstriction, water and sodium retention, enhancing the activity of the sympathetic system, and leading to an increase in blood pressure. Direct renin inhibitors can directly inhibit the production of renin, reduce the concentration of Ang II in the body, and antagonize the blood pressure-elevating effect of Ang II.

Aliskiren is currently the only direct renin inhibitor available on the market, which is safe and effective when used alone or combined with other drugs for hypertension treatment. However, Aliskiren has a relatively low oral bioavailability and a long synthetic pathway, which may lead to severe adverse reactions among patients in clinical practice. A new generation of direct renin inhibitor, SPH3127, jointly developed by the Academia Sinica, Shanghai Pharmaceuticals Holding Co., Ltd. (China), and Mitsubishi Tanabe Pharma Corporation (Japan), has improved oral bioavailability, high specificity, and relatively small adverse reactions. Preclinical pharmacological and toxicological studies have shown that this drug significantly outperforms similar products in terms of efficacy, bioavailability, and safety. Phase I clinical trials have proven that SPH3127 is safe for healthy subjects, and in Phase II clinical trials, SPH3127 demonstrated good efficacy and safety in patients with mild to moderate essential hypertension, supporting the advancement of SPH3127 tablets into Phase III clinical trials.

3.ETA/ETB Dual Endothelin Receptor Antagonists

Endothelin (ET) is a vasoconstrictor peptide composed of 21 amino acids and has three types: ET-1, ET-2, and ET-3. It acts on the vascular smooth muscle receptors ETA and ETB, which have distinct antagonistic effects. ET-1 acting on ETA can induce intense vasoconstriction in humans and mammals, as well as activate the RAAS and stimulate the release of catecholamines. Activation of ETA induces vasoconstriction, while activation of ETB stimulates the release of endothelial vasodilators, producing vasodilatory effects that counteract the vasoconstrictive effect of ETA.

Current research on endothelin receptor antagonists (ERAs) for the treatment of hypertension has shown that ERAs can be classified into two types: selective ERAs, such as ambrisentan, and non-selective ERAs, such as bosentan. Although bosentan can effectively lower blood pressure, its hepatotoxicity has hindered further use of the drug. Selective ERAs, such as ambrisentan, may be associated with fluid retention, renal failure, and the occurrence of heart failure.

Aprocitentan, a novel oral ETA/ETB receptor antagonist developed by Quantum Genomics SA, has a long half-life of 44 hours. It does not interfere with bile salt secretion and does not possess hepatotoxicity. Aprocitentan exerts its antihypertensive effect by influencing endothelin and its receptors, providing a new approach for the treatment of resistant hypertension. Currently, this drug is undergoing a Phase III clinical trial called PRECI-SION.

4.Novel Aminopeptidase A (APA) Inhibitors

APA and Aminopeptidase N (APN) are two membrane-bound zinc metalloproteinases that participate in the metabolism of brain Ang II and Ang III, respectively. APA cleaves the N-terminal aspartic acid from Ang II to form Ang III, while APN cleaves the N-terminal arginine from Ang III to form angiotensin IV (Ang IV). Both Ang II and Ang III have similar affinity for brain Ang II receptors and can cause an increase in blood pressure by activating sympathetic nervous activity, inhibiting the baroreflex at the level of the solitary tract nucleus, and increasing the concentration of arginine vasopressin in the blood.

In animal experiments, intracerebroventricular injection of the selective APA inhibitor EC33 was able to cause a decrease in blood pressure, suggesting that EC33 can block the pressor effect of Ang III. Compared to Ang II in the brain, Ang III has a stronger pressor effect. The novel Aminopeptidase A inhibitor Firibastat, developed by Quantum Genomics Pharmaceuticals in the United States, is a first-in-class antihypertensive drug. By delivering EC33 products to the brain, this drug specifically inhibits Aminopeptidase A, thereby reducing the production of Ang III and exerting a blood pressure-lowering effect. Currently, the company has published data from the Phase IIb clinical trial NEW-HOPE (NCT03198793) of Firibastat. The NEW-HOPE study suggests that Firibastat can be used as a safe and effective antihypertensive drug for the treatment of resistant hypertension.

5.Sodium-Potassium Ion Channel Transport Inhibitors

In the basolateral membrane of the renal tubules, the Na+-K+ pump serves as the driver for renal sodium reabsorption. Altering the function of the Na+-K+ pump can change the total blood volume, thereby leading to hypertension. Therefore, the renal tubular Na+-K+ pump is a potential new target for the treatment of hypertension. Research has shown that there are two factors that affect the function of the renal Na+-K+ pump in humans and rats: the endogenous cardiotonic steroid ouabain, a salt-regulating hormone, and the mutated cytoskeletal protein α-adducin. Both of these factors abnormally activate the Na+-K+ ion pump, promoting water-sodium retention and causing hypertension. Therefore, drugs targeting these two factors can counteract the effects of ouabain and mutated α-adducin on the function of the Na+-K+ pump.

Rostafuroxin is a safe and effective derivative of digoxin that inhibits the Na+-K+ ATPase-Src-EGFR-ERK signaling pathway activated by mutated α-adducin (rs4961, Trp460) or ouabain, and has the ability to normalize renal sodium transport. Rostafuroxin acts on the Src-SH2 domain, selectively inhibiting Src activation, and inhibits renal tubular sodium reabsorption by inhibiting related signaling pathways, thus exerting a blood pressure-lowering effect. The results of the PEARL-HT clinical trial showed that compared to a placebo, Rostafuroxin had no significant effect on systolic blood pressure in Chinese subjects. This suggests that Rostafuroxin may be used to guide the pharmacological treatment of primary hypertension in Caucasians, and further research is still needed for targeted treatment drugs for Chinese patients with primary hypertension.

6.Natriuretic Peptide Receptor Agonists

There are three natriuretic peptides (NPs) in the human body: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). NPs interact with three cell surface natriuretic peptide receptors (NPR-A, NPR-B, NPR-C) to mediate their biological effects. NPR-A and NPR-B are the primary functional receptors for NPs, which activate membrane-associated guanylate cyclases and produce the second messenger cyclic guanosine monophosphate (cGMP) in various cells and tissues. They participate in the regulation of multiple physiological processes in the body, including blood pressure, myocardial growth, neurodevelopment, bone development, etc. NPR-C, on the other hand, is a clearance receptor for NPs and has little relationship with cGMP. ANP and BNP are potent agonists for the NPR-A receptor, while CNP selectively binds to NPR-B to exert its effects. NPs in the human body are rapidly degraded by neutral endopeptidase (NEP) and internalized for clearance via the clearance receptor NPR-C. NPs have the biological properties of diuresis, natriuresis, and vasodilation, and play a direct role in regulating blood pressure homeostasis.

Palatin Technologies, a pharmaceutical company in the United States, has developed PL-3994, a new selective natriuretic peptide receptor agonist. Clinical trials have demonstrated that PL-3994 has high affinity for both recombinant human, dog, or rat NPR-A and human NPR-C, but has no effect on human NPR-B. Unlike the natural NP ligands ANP and BNP, PL-3994 has a lower affinity for the clearance receptor NPR-C than for NPR-A.

7.Dopamine β-Hydroxylase (DβH) Inhibitors

The occurrence of primary hypertension is closely related to excessive activation of the sympathetic nervous system, leading to excessive elevations in norepinephrine. The use of adrenergic receptor blockers has a certain therapeutic effect on primary hypertension. DβH is the final step in the synthesis of epinephrine in humans and animals, so inhibiting DβH can reduce the production of epinephrine to a certain extent, thereby lowering blood pressure. DβH inhibitors can exert vasodilatory effects on renal blood vessels and induce diuresis by gradually inhibiting the sympathetic nervous system, improving renal function to a certain extent while lowering blood pressure.

Etamicastat, also known as BIA 5-453, is a new generation of DβH inhibitors that plays a role in the treatment of cardiovascular diseases such as hypertension, coronary heart disease, and heart failure. Etamicastat is a reversible DβH inhibitor with limited access to the brain, primarily exerting its effects peripherally by reducing norepinephrine levels.

8.Soluble Guanylate Cyclase (sGC) Stimulators

sGC is a key signaling enzyme in the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway. After NO binds to sGC, it activates sGC, and the activated sGC catalyzes the conversion of GTP into cGMP. cGMP, as a second messenger, can regulate various downstream effector molecules, causing vasodilation and participating in the regulation of multiple physiological functions of the cardiovascular system. It is closely related to the occurrence of various cardiovascular diseases such as heart failure, hypertension, pulmonary arterial hypertension, atherosclerosis, and peripheral vascular diseases. The small signaling molecule NO has disadvantages such as a short duration of existence, easy formation of tolerance with receptors, and possible production of peroxynitrite. sGC stimulators can act directly on sGC without relying on NO, and they can also synergize with NO to enhance the activity of cardiomyocytes to endogenous factors.

Riociguat and Vericiguat are representative drugs of sGC stimulators. Animal experiments have confirmed that Riociguat has blood pressure-lowering and target organ-protecting effects, including the heart and kidneys, in both high-renin and low-renin hypertensive rat models. Currently, among all sGC stimulators, Vericiguat has been extensively studied for the treatment of heart failure. The VICTORIA study, published by Bayer in Germany and Merck & Co. in the United States, confirmed that Vericiguat can reduce hospitalization rates and mortality due to adverse cardiovascular events in high-risk patients with heart failure and reduced ejection fraction, providing a new treatment approach for patients with heart failure combined with hypertension.

References

[1] Liu Guijian, Cheng Kuan, Zhu Wenqing, Ge Junbo. Progress in the Pharmacological Treatment of Hypertension [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(04): 446-449.

[2] Luo Xiaoyang, Liu Wei. Research Progress in New Antihypertensive Drugs [J]. Shandong Medical Journal, 2021, 61(29): 88-92.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.