Aliskiren
First direct renin inhibitor for hypertension, blocking the rate-limiting step of the renin-angiotensin-aldosterone system.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | C30H53N3O6 |
| Molecular Weight | 551.8 Da |
| CAS Number | 173334-57-1 |
| Peptide Class | Renin Inhibitor (Non-peptide mimetic) |
| Route | Oral |
Structure
Aliskiren (Tekturna) is a non-peptide, orally active direct renin inhibitor. It was designed using structure-based drug design to mimic the transition state of angiotensinogen cleavage by renin. The molecule contains a hydroxyethylene isostere that binds the renin active site with high affinity.
Mechanism of Action
Aliskiren binds the active site of renin, blocking the cleavage of angiotensinogen to angiotensin I. This inhibits the rate-limiting step of the RAAS, reducing Ang I and Ang II production. Unlike ACE inhibitors and ARBs, aliskiren does not cause compensatory renin elevation.
Clinical Applications
- Hypertension: Monotherapy or combination with other antihypertensives
- Type 2 diabetic nephropathy: ALTITUDE trial (terminated early)
- Heart failure: ASTRONAUT trial (no benefit, possible harm)
- Limited clinical use: Due to trial results and cost
Pharmacokinetics
- Half-life: 24-40 hours
- Tmax: 1-3 hours
- Bioavailability: 2.5% (low)
- Metabolism: Minimal CYP involvement
- Elimination: Fecal (primarily)
- Route: Oral (150-300 mg daily)
Safety and Side Effects
Diarrhea (2.3%), cough (1.1% - lower than ACE inhibitors), hyperkalemia (especially with ACE inhibitors/ARBs), hypotension, and angioedema (rare). Contraindicated with ACE inhibitors or ARBs in diabetes (ALTITUDE trial).
References
- Weir, M.R., et al. (2008). Aliskiren for hypertension. American Journal of Hypertension, 21, 1018-1024.
- Parving, H.H., et al. (2012). ALTITUDE trial: aliskiren in type 2 diabetes. New England Journal of Medicine, 367, 2204-2213.
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