Compound M24 is a selective angiotensin II AT2 receptor agonist with a Ki value of 0.4 nM for the AT2 receptor. Compound enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. In a mouse model of atherosclerosis, plaque size and stability were improved in ApoE‐/‐ mice treated with M24. Treatment with M24 resulted in decrease in scar size and reduction in markers of inflammation in a rat model of myocardial infaction.

VTP-27999 is an alkyl amine renin inhibitor. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans. Vitae Pharmaceuticals was developing VTP 27999 for the treatment of chronic kidney disease. VTP 27999 was in phase I clinical development in the US. However, the product is no more on the company pipeline and it appears that the development has been discontinued.

Secoisolariciresinol diglucoside (SDG) isolated from flaxseed is a lipid-lowering and antioxidant agent. It suppresses the development of hypercholesterolemic atherosclerosis in rabbits. Secoisolariciresinol diglucoside has been shown to have antioxidant and cardioprotective properties. SDG interferes with the development of different types of diseases like cardiovascular, diabetic, lupus nephritis, bone, kidney, menopause, reproduction, mental stress, immunity, atherosclerosis, hemopoietic, liver necrosis and urinary disorders due to its various biological properties including anti-inflammatory, antioxidant, antimutagenic, antimicrobial, antiobesity, antihypolipidemic and neuroprotective effects. Moreover, SDG has a defending mediator against various cancers by modulating multiple cell signaling pathways. The animal and human studies have shown the prevention role of SDG against some cancers (breast, lung and colon) as a result of its strong anti-proliferative, antioxidant, anti-oestrogenic and/or anti-angiogenic activity. It is proposed that the anticancer activity of SDG is associated with the inhibition of enzymes involved in carcinogenesis. Human studies showed the SDG as potential cardiovascular protector by mediating the mechanisms of total cholesterol, LDL-cholesterol, HDL-cholesterol, triacylglycerides and glucose metabolism. It was observed that 20 hypercholesterolaemia and hypertriglyceridaemia subjects receiving 600 mg SDG per day for 8 weeks led to significant reductions in total cholesterol, LDL-cholesterol and glucose concentrations compared with the placebo group. The animal and human studies revealed that high fat diet containing 0 · 5 to 1 · 0 % SDG reduces liver triglycerides content, serum triglycerides, total cholesterol, and insulin and leptin concentrations that resulted in significantly reduced visceral fat gain as compared to group of mice receiving high fat diet without SDG. SDG reduces C-reactive protein concentrations which are associated with insulin resistance and diabetes mellitus in type 2 diabetics. Daily consumption of low-fat muffin enriched with SDG (500 mg/day) for 6 week can reduce CRP concentrations. SDG has long acting hypotensive effect mediated through the guanylate cyclase enzyme.

SAR407899 is a potent, ATP-competitive Rho kinase inhibitor. It antihypertensive action in animals. Sanofi is developing SAR 407899 for the treatment of microvascular angina (Syndrome X). It was previously being developed in clinical trials for the treatment of diabetic neuropathies, diabetic nephropathies, erectile dysfunction, pulmonary hypertension, hypertension and kidney disorders, but development was discontinued for those indications.

ICI-118,551 is a selective subtype β2 adrenergic receptor (adrenoreceptor) antagonist. ICI-118,551 binds to the β2 subtype with at least 100 times greater affinity than to other subtypes of the beta adrenoceptor β1 or β3. Pharmacological experiments proved that the right shift of the norepinephrine dose-response curve by ICI-118,551 was mediated via a beta(2)-adrenoceptor/G(i/o) protein-dependent pathway enhancing NO production in the endothelium. These results were corroborated in beta-adrenoceptor and endothelial NO synthase knockout mice where ICI had no effect. ICI-118,551 increased vascular lumen diameter in lung sections and reduced pulmonary arterial pressure under normoxia and under hypoxia in the isolated perfused lung model. These effects were found to be physiologically relevant, because ICI-118,551 specifically decreased pulmonary but not systemic blood pressure in vivo. Thus, it has been suggested that ICI-118,551 is a pulmonary arterial-specific vasorelaxant and might be a potential novel therapeutic agent for the treatment of pulmonary arterial hypertension. It was also demonstrated that systemic topical administration of ICI 118,551 results in decreased intraocular pressure in both eyes of rabbits, indicating that at least part of the ocular hypotensive effect of topical ICI 118,551 is mediated through systemic absorption. However, ICI 118,551 did not lower blood pressure in hypertensive patients known to respond to therapy with atenolol or propranolol.

Pterostilbene is a naturally derived compound found primarily in blueberries and Pterocarpus marsupium heartwood. The multiple benefits of pterostilbene in the treatment and prevention of human disease have been attributed to its antioxidant, anti-inflammatory, and anti-carcinogenic properties leading to improved function of normal cells and inhibition of malignant cells. The antioxidant activity of pterostilbene has been implicated in anti-carcinogenesis, modulation of neurological disease, anti-inflammation, attenuation of vascular disease, and amelioration of diabetes. Pterostilbene increases LDL and reduces blood pressure in adults. Low doses of pterostilbene seem to hold some benefit for cognition.

Puerarin (7, 4’-dihydroxyisolavone-8-β-glucopyranoside) is an active isoflavone extracted from the roots of Pueraria lobata (Willd.) Ohwi. Puerarin is widely used in traditional Chinese medicine, and is clinically used in China for the treatment of coronary artery disease, heart failure, hypertension and myocardial infarction. It has been reported that puerarin had therapeutic effects on diabetes mellitus, arteriosclerosis and myocardial ischemia in animals. Puerarin demonstrated beta-adrenergic receptor blocking effect. On the other hand, puerarin stimulated alpha1-adrenoreceptor to increase glucose uptake into cultured C2C12 cells of mice. Puerarin has been investigated for the treatment (phase II clinical trials) of Alcohol Abuse, Rheumatoid Arthritis and Hypertension.

Z-Chlorogenic acid better known as cis-5-caffeoylquinic acid is a cinnamate ester formed by condensation fo the carboxy group of cis-caffeic acid with the 5-hydroxy group of (+)-quinic acid. It is a naturally occurring isomer of Chlorogenic acid and can be extracted from Nerium indicum flowers, coffee plant, Purpurascen leaves, Artemisia pectinata, and tobacco. In some but not all extractions cis-5caffeoylquinic content is increased after UV exposure of plant or cells.

Indolapril (CI-907) is a new orally active prodrug of nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, developed by Warner-Lambert/Parke-Davis Pharmaceutical Research for treating hypertension. Indolapril is epimer of trandolapril, well-known ACE inhibitor currently in the market for hypertension treatment. Indolapril (Monoester form) and it’s active component (diacid form) produced concentration related ACE inhibition in guinea-pig serum (IC50 for monoester -- 0.1 mkM and for diacid -- 2.6 nM). In isolated rabbit aortic rings and in rat and dog autonomic studies, Indolapril is highly specific in suppressing the contractile or pressor responses to angiotensin I. In two-kidney, one-clip Goldblatt hypertensive rats, single daily doses (0.03-30 mg/kg p.o.) produced dose-dependent decreases in blood pressure; 3 mg/kg lowered blood pressure to normotensive levels. In the spontaneously hypertensive rat, subacute administration of Indolapril produced the same decrease in blood pressure as that obtained in the renal hypertensive rat. In diuretic-pretreated renal hypertensive dogs, 10 mg/kg normalized blood pressure. For equivalent drops in blood pressure, heart rate increases were less in Indolapril than in enalapril-treated renal hypertensive dogs. No side effects were observed with CI-907 in any of the conscious animals. The antihypertensive response to Indolapril (0.03-1.0 mg/kg p.o.) was found to correlate with inhibition of vascular tissue ACE, but not plasma or brain ACE in two-kidney, one-clip renal hypertensive rats.

Apocynin, also known as acetovanillone, is a natural organic compound related to vanillin. It has been isolated from a variety of plant sources. Metabolites of apocynin are able to block the activity of NADPH oxidase, thus giving apocynin antioxidant and anti-inflammatory capabilities. Effects of apocynin on the concentration of reactive oxygen and nitrogen species in patients with asthma and chronic obstructive pulmonary disease were investigated in phase I clinical trials. In preclinical models, it was found that apocynin provides neuroprotective effects in models of stroke and Parkinson's disease.