Discovery and development of statins

Hypercholesterolemia is considered to be one of the major risk factors for atherosclerosis which often leads to cardiovascular, cerebrovascular and peripheral vascular diseases.

[2] In the mid-19th century, a German pathologist named Rudolf Virchow discovered that cholesterol was to be found in the artery walls of people that died from occlusive vascular diseases, like myocardial infarction.

There is no build-up of potentially toxic precursors when HMGR is inhibited, because hydroxymethylglutarate is water-soluble and there are alternative metabolic pathways for its breakdown.

[2][3] In the 1970s the Japanese microbiologist Akira Endo first discovered natural products with a powerful inhibitory effect on HMGR in a fermentation broth of Penicillium citrinum, during his search for antimicrobial agents.

[2] Statins are a competitive antagonists of HMG CoA, as they directly compete with the endogenous substrate for the active site cavity of HMGR.

[7] The essential structural components of all statins are a dihydroxyheptanoic acid unit and a ring system with different substituents.

Simvastatin and lovastatin are inactive lactones which must be metabolized to their active hydroxy-acid forms in order to inhibit HMGR.

In addition to the polar interaction, Lys691 participates in a hydrogen bonding network with Glu559, Asp767 and the O5 hydroxyl group of the hydroxyglutartic acid component of the statins.

Van der Waals interactions are formed between the hydrophobic side chains of the enzyme, which involve the Leu562, Val683, Leu853, Ala856 and Leu857 and the statins.

The newest statin, rosuvastatin has a unique polar methane sulfonamide group, which is quite hydrophilic and confers low lipophilicity.

As a result, rosuvastatin has superior binding affinity to the HMGR enzyme compared to the other statins, which is directly related to its efficiency to lower LDL cholesterol.

[7] It has been reported that the organic anion transporting polypeptide (OATP) is important for the hepatic uptake of hydrophilic statins such as rosuvastatin and pravastatin.

[13] With the recent elucidation of the structures of the catalytic portion of human HMGR enzyme complexed with six different statins by a series of crystallography studies, new possibilities have opened up for the rational design and optimization of even better HGMR inhibitors.

[15] A new study using comparative molecular field analysis (CoMFA) to establish three-dimensional quantitative structure-activity relationship (3D QSAR), while searching for novel active pharmacophores as potentially potent HGMR inhibitors, was recently published.

This structure-based virtual screening procedure is considered promising for rational quest and optimization of potential novel HGMR inhibitors.