Blog

Four AT2 receptor agonists are under preclinical investigation:

• One is a nonpeptide agonist compound 21 (C21) : Treatment with C21 for 7 days resulted in a significant improvement in heart function. The protective effect of C21 on renal damage was observed in spontaneously hypertensive rats (SHRs)
• Three are peptidergic agonists: β-Tyr4-Ang II, β-Ile5-Ang II, and LP2-3.

Two molecules are in the preclinical investigation:

• The peptide Ang (1-7) acts through the proto-oncogene MasR, a G protein-coupled receptor. The ACE2/Ang(1-7)/ MasR axis demonstrates protective action, as it minimizes the harmful actions of the classic ACE/Ang II/AT1R axis.
• The ACE2 activator diminazene aceturate (DIZE) suppresses hemodynamic and morphological alterations in a myocardial infarction rat model. It also had a protective effect on cardiac and histopathological manifestations in rats and is beneficial in arrhythmias, such as electrophysiological dysfunction.

Two molecules are under clinical investigation:

• Recombinant human ACE2 (rhACE2) - in a diabetic mouse model, rhACE2 showed promising results in reducing the progression of diabetic nephropathy. It also lowered high BP and reduced the progression of cardiac fibrosis in hypertensive animal models.
• GSK 2586881 - Pulmonary arterial hypertension is being tested.

pGC-A activator/designed natriuretic peptide (NP)

• CRRL269 - demonstrated vasorelaxation and antihypertensive effects on the renal and cardiac system model of ischemia-induced acute kidney injury in canines.
• ZD100 . It demonstrated to be highly efficacious and safe in reducing BP with a single subcutaneous administration in a human study with significant renal protective function and reduced aldosterone levels.
• ANX042 - was proven to be safe in healthy volunteers, and it was shown to activate the secondary messenger cGMP.

Vasopeptidase Inhibitors (VPi) ( are ACEi-NEPi combination)

• Omapatrilat is the most studied VPi, but it has failed in clinical trials due to the side effects of angioedema.
• Ilepatril (AVE 7688) VPi has entered a phase 3 clinical trial.

Angiotensin Receptor Neprilysin inhibitor (ARNi) class

• LCZ696 (Sacubitril/Valsartan) is the prototype of the ARNi class. This drug was proven to be devoid of any severe side effects of angioedema, as it halts the metabolism of bradykinin. It was found to be superior to the ARB enalapril in cardio protection. The ARNi improved outcomes in cardiac dysfunction and suppressed cardiac hypertrophy, fibrosis and vasculopathy. In 2015 was approved by the USFDA for the treatment of cardiovascular disorders.

• Riociguat - was the first sGC stimulator to be introduced. It is used in the treatment of different forms of pulmonary hypertensive conditions.
• Heme-free BAY 58-2667 - In experimental chronic heart failure conditions, has effective systemic and renal vasorelaxant actions. It also significantly improves cardiac output, glomerular filtration rate (GFR), natriuresis and diuresis in chronic heart.
• Other promising sGC stimulators such as vericiguat (BAY 60-4552), BAY 41-8543, BI 703704, Cinaciguat, GSK2181236A, and Ataciguat have also shown prominent protective action in severe pathological conditions. In addition, sGC stimulators have promising antifibrotic, antihypertrophic and anti-inflammatory effects.

• Firibastat is a selective APA. When orally administered firibastat prodrug crosses the gastrointestinal and blood-brain barriers and enters the brain, it produces two molecules that inhibit brain APA activity, block brain Ang III formation, and control BP. In addition, it reduced BP in preclinical models of hypertension. This drug was useful in the downregulation of plasma AVP, increases diuresis and natriuresis, and thus promotes a decline in blood volume.
• NI956/ QGC006 is a new centrally acting APA inhibitor that is more effective than Firibastat in lowering BP. Extensive preclinical and clinical trials show the efficacy and safety of APA inhibitors, resulting in a sustained decrease in BP via downregulation of systemic AVP release and sympathetic activity and improvement in the baroreflex function of hypertensive animal.
• PC-18 significantly inhibited the natriuretic response in AT1 receptor-blocked rats. Renal interstitial infusion of PC-18 also ameliorated defective AT2 receptor-mediated natriuresis and hypertension in young SHRs

• HFI-419 provides a new treatment for well-known cardiac diseases, leading to improved target organ function. HFI-419 offers improved antifibrotic efficacy and renoprotection compared to candesartan cilexetil (CAND). HFI-419 also proved safer and showed better antifibrotic efficacy than the ACE inhibitor perindopril (PERIN) in murine high salt-induced kidney damage.