with the endogenous substrate for the active site cavity of HMGR. Statins are also noncompetitive with the cosubstrate NADPH (nicotinamide adenine dinucleotide phosphate). By blocking the HMGR enzyme they inhibit the synthesis of cholesterol via the mevalonate pathway. The end result is lower LDL (Low Density Lipoprotein), TG (Triglycerides) and total cholesterol levels as well as increased HDL (High Density Lipoprotein) levels in serum. Interactive pathway map Statin drug design The ideal statin should have the following properties: High affinity for the enzyme active site Marked selectivity of uptake into hepatic cells compared with non-hepatic cells Low systemic availability of active inhibitory equivalents Relatively prolonged duration of effect. One of the main design objectives of statin design is the selective inhibition of HMGR in the liver, as cholesterol synthesis in non-hepatic cells is needed for normal cell function and inhibition in non-hepatic cells could possibly be harmful. The statin pharmacophore The essential structural components of all statins are a dihydroxyheptanoic acid unit and a ring system with different substituents. The statin pharmacophore is modified hydroxyglutaric acid component, which is structurally similar to the endogenous substrate HMG CoA and the mevaldyl CoA transition state intermediate (Figure 1). The statin pharmacophore binds to the same active site as the substrate HMG-CoA and inhibits the HMGR enzyme. It has also been shown that the HMGR is stereoselective and as a result all statins need to have the required 3R,5R stereochemistry. Differences in statin structure The statins differ with respect to their ring structure and substituents. These differences in structure affect the pharmacological properties of the statins, such as: Affinity for the active site of the HMGR Rates of entry into hepatic and non-hepatic tissues Availability in the systemic circulation for uptake into non-hepatic tissues Routes and modes of metabolic transformation and elimination Statins have sometimes been grouped into two groups of statins according to their structure. Type 1 statins Statins that have substituted decalin-ring structure that resemble the first statin ever discovered, mevastatin have often been classified as type 1 statins due to their structural relationship. Statins that belong to this group are: Lovastatin (Figure 2) Pravastatin Simvastatin Type 2 statins Statins that are fully synthetic and have larger groups linked to the HMG-like moiety are often referred to as type 2 statins. One of the main differences between the type 1 and type 2 statins is the replacement of the butyryl group