Aliskiren

Aliskiren (brand names Tekturna and Rasilez) is the first in a class of drugs called direct renin inhibitors. It is used for essential (primary) hypertension.^[1]

Aliskiren is an antagonist to renin.^[2] Renin, the first enzyme in the renin–angiotensin–aldosterone system, plays a role in blood pressure control. It cleaves angiotensinogen to angiotensin I, which is in turn converted by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following, thereby increasing plasma volume, and thus blood pressure.^[2]

(2v0z).

. Water molecules are shown as red spheres.

Aliskiren is a hydrophilic molecule. When bound to renin, aliskiren occupies the S1, S1', S2', and S3 hydrophobic regions of renin. Most importantly aliskiren occupies the S3^SP region that is equally hydrophobic and hydrophilic and greatly increases binding affinity.^[3] Aliskiren interacts with multiple residues in renin. The hydroxyl group hydrogen bonds both oxygens. The methoxy group in the S3 hydrophobic region hydrogen bonds to secondary amine group of . The amide group hydrogen bonds with the secondary amine of .^[4] And the terminal amide hydrogen bonds with in the S2' hydrophobic pocket.^[5]

There are three generations of renin inhibitors. The first two generation molecules were peptide molecules. These peptide molecules were not specific or effective as renin inhibitors. Aliskiren, part of the 3^rd generation, is a nonpeptide renin inhibitor. Small molecule nonpeptide inhibitors such as aliskiren have good pharmokenetics and are very specific for renin and not other protein peptidases. Advancements in crystallography and molecular modeling allowed the discovery of aliskiren. Aliskiren inhibits renin activity. Since renin is the rate limiting step of the RAS renin inhibition is a successful method to lower blood pressure.

Aliskiren is approved by the Federal Drug Administration (FDA) to treat hypertension.

The structure of renin bound with the inhibitor aliskiren has been solved using X-ray diffraction at 3.0 Å resolution.^[6]