Renin Inhibition With Aliskiren

Abstract

1. Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modelling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors, such as aliskiren. 2. Aliskiren has a low bioavailability (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23-36 h), which makes it suitable for once-daily dosing. 3. The once-daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 (AT1) receptor blockers (losartan, valsartan, irbesartan), hydrochlorothiazide, angiotensin converting enzyme inhibitors (ramipril and lisinopril) or long acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, irbesartan or ramipril. 4. The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme (ACE) inhibition and Ang II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cyclic guanosine monophosphate pathway and possibly the (pro)renin receptor. 5. Blockade of the renin angiotensin system (RAS) with ACE inhibitors, AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize RAS blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the RAS fully quiescent is a new possibility requiring further study.

How are physicians prescribing the direct renin inhibitor aliskiren in the management of essential hypertension? A French observational study

“…Furthermore, it shows that aliskiren is mostly prescribed to replace another drug. Aliskiren, like ARBs and ACEis, blocks the renin-angiotensin system (RAS), although each class of drug acts at a different point of the pathway [9]. Accordingly, when aliskiren was prescribed to replace another drug, the most common classes replaced were ARBs and ACEis.…”

“…Since these guidelines were compiled, a new drug, aliskiren, has been shown to be well tolerated and effective in the management of hypertension [7,8]. Aliskiren is a direct renin inhibitor [9] and constitutes an entirely new therapeutic class of antihypertensive drug. In the course of its development, it was shown to be significantly more effective on its own than either an inhibitor of angiotensin-converting enzyme (ramipril) [10,11] or a diuretic (hydrochlorothiazide) [12] and it afforded add-on efficacy when combined with all of the existing classes of antihypertensive drug [13].…”

Direct Renin Inhibitors as Antihypertensive Agents

“…Increasing evidence indicates that inhibition of the RAAS is an effective way to control high BP and intervene in the pathogenesis of CV disorders, diabetic 1 kidney disease, and atherogenesis. 2,3 Although, blockade of the RAAS with angiotensin converting enzyme (ACE) inhibitors, angiotensin II AT1 receptor blockers (ARBs), or a combination of these drugs has become one of the most successful therapeutic approaches in medicine, 4 the ACE inhibitors and ARBs do not completely suppress the RAAS, because of the compensatory rise in plasma renin activity (PRA). 5 Based on studies using very high-dose ARB or combination therapy with ACE inhibitor and ARB, it has been suggested that more complete blockade would lead to improved clinical outcomes.…”

Development of accurate binding affinity predictions of novel renin inhibitors through molecular docking studies

“…Molecular modeling and determination of the X-ray crystallographic structure of the active site of renin have led to the identification of new renin inhibitors [9,10]. The first representative of this class of non-peptide drugs is aliskiren, an orally active, renin inhibitor with a very high binding affinity for renin [11][12][13][14]. Aliskiren received approval but still it is a complicated molecule with many steps to be synthesized.…”