173334-58-2

Last March, the U.S. became the first country to approve Tekturna® (aliskiren fumarate; Novartis/Speedel), a first-inclass antihypertensive agent. The once-daily, oral, direct renin inhibitor received FDA approval for treatment of high blood pressure as mono therapy or in combination with other antihypertensive medications.Furthermore, aliskiren demonstrated increased efficacy when used in combination with other commonly used blood pressure-lowering medications. Novartis is conducting a large outcome trial program to evaluate the long-term effects of aliskiren and of direct renin inhibition in general.

White Solid

Aliskiren hemifumarate is a direct renin inhibitor with IC50 of 1.5 nM

An orally active, synthetic nonpeptide renin inhibitor. Antihypertensive.

ChEBI: The hemifumarate salt of aliskiren.

Renin inhibitor:
Hypertension

The synthesis of aliskiren by Novartis is depicted in the scheme.Aliskiren (I) was synthesized through a convergent synthetic strategy by coupling key intermediate chloride 5 with aldehyde 10. Hydrogenation of cinnamic acid 1, followed by generation of the acid chloride of the corresponding acid and reaction with (+)-pseudoephedrine provided amide 2 in 91% yield. Deprotonation of amide 2 with LDA followed by alkylation with 2-iodopropane in refluxing THF gave 3 as a single diastereomer in 52% yield. Reduction of the amide functionality in 3 using n-butyl lithium boron trifluoride ammonium complex proceeded without epimerization of the chiral center to give alcohol 4 in 66% yield. Chlorination of 4 using phosphorus oxychloride gave chloride 5, in 78% yield as the organometallic precursor for the eventual coupling to aldehyde 10. Synthesis of fragment 10 commenced with (+)-pseudoephedrine isovaleramide 6, which was efficiently deprotonated with LDA and alkylated using allyl bromide; diastereomerically pure 7 was obtained upon crystallization of the crude reaction mixture in 78% yield. Bromolactonization of 7, using n-bromosuccinimide in the absence of acetic acid gave amide acetal 8 with a single configuration at the spirocenter and a 6:1 mixture of trans:cis ring substituents. Displacement of the bromide using tetrabutylammonium acetate followed by basic hydrolysis provided alcohol 9 in 85% yield. Oxidation of 9 using dimethyl sulfoxide-sulfur trioxide/pyridine proceeded without epimerization to furnish the masked lactone aldehyde 10 in 60% yield. Coupling of fragments 5 and 10 was achieved by treatment of 10 with the organocerium reagent of the corresponding Grignard reagent prepared from 5. Hydrolysis of the crude spirocyclic addition product revealed that the hydroxylactone 11 was formed in 51% overall yield as an inseparable epimeric mixture with a Felkin-Anh selectivity of 85:15. The requisite nitrogen functionality was installed via the brosylate to give azido lactone 12 in 68% yield. Aminolysis with 3-amino-2,2-dimethylpropionamide led to formation of the open chain azido alcohol 13 in 76% yield. The synthesis of aliskiren was completed by azide hydrogenolysis and formation of the hemifumarate salt. Generation of pure aliskiren was achieved via crystallization which removed the residual minor (R)-epimer carried through from the Grignard addition step to afford aliskiren (I) in 43% yield.

Potentially hazardous interactions with other drugs
Other antihypertensive agents: enhanced antihypertensive effect; concentration possibly reduced by irbesartan; increased risk of hyperkalaemia and hypotension with ACE-Is and ARBs.
Antifungals: concentration increased by itraconazole and ketoconazole, avoid with itraconazole.
Ciclosporin: concentration of aliskiren increased - avoid.
Diuretics: may reduce concentration of furosemide; hyperkalaemia with potassium-sparing diuretics.
Grapefruit juice: concentration of aliskiren reduced - avoid.
Heparins: increased risk of hyperkalaemia.
Potassium salts: increased risk of hyperkalaemia.

Approximately 1.4% of the total oral dose is metabolised by CYP3A4. Approximately 0.6% of the dose is recovered in urine following oral administration. Aliskiren is mainly eliminated as unchanged compound in the faeces (78%).

Store at -20°C