4. Discussion
Hypertension is a chronic cardiovascular disease characterized by elevated systolic and/or diastolic blood pressure. It is a major risk factor for various cardiovascular diseases. A high-salt diet is closely associated with hypertension, and its mechanism of action is complex. ARNi is a novel type of antihypertensive medication with a unique mechanism of action. The first ARNi drug, LCZ696, has been reported to have significant antihypertensive effects, particularly in patients with salt-sensitive hypertension, and its clinical efficacy in reducing blood pressure is significantly better than that of olmesartan, an angiotensin receptor blocker (ARB) [12]. S086, a new generation of ARNi product developed by Salubris, has validated anti-heart failure effects in preclinical MI chronic heart failure models and completed phase 1 clinical trial [17-18]. We investigated the antihypertensive effect of S086 compared to LCZ696 using the DSS rat model of hypertension and explored the diuretic and natriuretic effects of ARNi drugs. Additionally, we used real-time telemetry system for blood pressure measuring, providing a more accurate reflection of rats’ real-time blood pressure status and avoiding blood pressure fluctuations caused by traditional animal manipulation methods.
Our study found that peak blood pressure values for both DSS rats and normal rats occurred between 9:00 PM and 2:00 AM, and trough values occurred between 1:00 PM and 6:00 PM. This indicates a significant difference from the circadian rhythm of human blood pressure, which peaks between 12:00 PM and 6:00 PM and has trough values between 1:00 AM and 4:00 AM according to clinical research [20-21]. Differences in blood pressure rhythms between rats and humans may be due to differences in their circadian activity rhythms. Rodents are typically active and eat at night and rest during the day, while humans are generally active and eat during the day and rest at night. Our administration of compounds to DSS rats at 11:00 AM is equivalent to humans taking medication before bedtime at 11:00 PM, which has certain guiding significance for the timing of administration in future rodent models of hypertension. If we aim to fully simulate human clinical medication habits (taking medication in the morning), we suggest administering animals during 5:00-6:00 PM [22-23].
The new generation of ARNi drug-S086 demonstrated significant antihypertensive effects in the DSS rat model of hypertension, dose-dependently reducing both systolic and diastolic blood pressure (Figure 2, Figure 3). In the DSS hypertensive rat model, a high-salt diet leads to sodium and water retention, resulting in increased blood volume and elevated blood pressure. Furthermore, studies have reported that a high-salt diet directly activates the renin-angiotensin-aldosterone system (RAAS), which is an additional mechanism contributing to the development of high blood pressure [24]. S086, composed of an ARB and NEP inhibitor, can directly inhibit the RAAS system while activating the natriuretic peptide system, ultimately lowering blood pressure. Compared to LCZ696 (69 mpk), the middle dose of S086 (23 mpk) demonstrated significantly superior antihypertensive efficacy at certain time points (Figure 4). This can be attributed to the superior activity of its ARB component, EXP3174, against the AT1 receptor, as well as its longer half-life. [18,25-26]. This indicates that S086 has the potential to be a more effective ARNi antihypertensive medication than LCZ696 for patients with hypertension. Additionally, the antihypertensive effects of S086 are even better than those of an equimolar dose of EXP3174 for two reasons. Firstly, S086 metabolizes into EXP3174 and sacubitril. Sacubitril further metabolizes into LBQ657- NEP inhibitor, and both of EXP3174 and LBQ657 reduce blood pressure through different mechanisms. Although the antihypertensive effect of the NEP inhibitor is relatively moderate, it is still stronger than that of the separate dose of EXP3174. Secondly, sacubitril increases the exposure level of EXP3174, resulting in a higher exposure after administering an equimolar dose of S086 [17].
LBQ657 as a neprilysin inhibitor has been reported significantly increases the expression of ANP and other natriuretic peptides in the body [27]. Upon metabolism into LBQ657, S086 activates the natriuretic peptide system, resulting in natriuresis and diuresis [28]. EXP3174, a high potent ARB metabolized from S086, has been shown to have a natriuretic effect [29]. We investigated the effects of each compound on water consumption, natriuresis and diuresis in the DSS model. The results indicated that each treatment group showed a slight decrease in water consumption compared to the vehicle group. This decrease may be attributed to the drug’s natriuretic and diuretic effects, leading to differences in salt and water balance in the body. With regard to the natriuresis and diuresis study, significant natriuretic and diuretic effects were observed in all treatment groups on the first dosing day (P<0.001, P<0.01, P<0.05). However, over time, the intensity of these effects gradually diminished, which aligns with the trend observed in clinical studies of LCZ696 in patients with salt-sensitive hypertension. In that study, compared to valsartan monotherapy, LCZ696 showed significant increases in natriuresis and diuresis on the first day after administration, which could not be sustained [12]. However, we observed antihypertensive efficacy with sacubitril (pro-drug of LBQ657) monotherapy, especially after 14-28 days of treatment, when its effect was stronger than after 7 days. This suggests that the antihypertensive effect of NEPi may not be solely due to natriuresis and diuresis, but rather from vasodilation. ANP and BNP can activate receptors expressed in peripheral blood vessels, leading to vasodilation. ANP and BNP can also inhibit aldosterone release, blocking the downstream signaling pathway of the RAAS system, which finally lead to antihypertensive effect [30]. However, the inhibitory effect of NEPi on the downstream signaling of the RAAS system activates the body’s negative feedback regulation mechanism, promoting the activity of upstream signals of the RAAS system, thereby activating the RAAS system. Therefore, NEPi’s antihypertensive effect alone is slight and must be used in combination with RAAS system blockers. The first-generation NEPi-omapatrilat simultaneously inhibited both NEP and ACE to activate the natriuretic peptide system and inhibit the RAAS system. However, due to the accumulation of bradykinin (a substrate of NEP and ACE) in the body, causing severe vascular edema, the drug was ultimately withdrawn from the market [31-32].
NEPi and ARB combine to form a cocrystal, which reduces the risk of vascular edema caused by omapatrilat (NEPi and ACE). The cocrystal form has better drug properties than physical mixtures since it improves solubility, enhances compound PK properties, and increases absorption [33-34]. We developed S086-a novel ARNi cocrystal, which improved EXP3174’s poor PK profile. Preclinical studies validated its significant blood pressure-reduction effect, superior to LCZ696. Completed phase 1 clinical trial demonstrated that S086 is well-absorbed in the human body, exhibits linear absorption, and can significantly affect target-related biomarkers. These provide solid foundation for conducting further clinical studies. We will explore S086’s antihypertensive effect in future phase 2 and phase 3 clinical trials, providing better treatment options for hypertension patients.