內容目錄
HMG-CoA reductase is the rate-limiting enzyme for cholesterol biosynthesis in the body, and is an important target for drugs that regulate blood lipids.
HMG-CoA reductase inhibitors, both natural and synthetic, contain 3,5-dihydroxycarboxylic acid pharmacophore, 5 of 3,5-dihydroxycarboxylic acid in the molecule. The hydroxyl group sometimes forms a lactone with a carboxyl group, and the lactone can only be effective after hydrolysis, which can be regarded as a prodrug, and the absolute configuration of the 3,5-dihydroxyl group is very important for the production of drug efficacy. effect.
Currently clinical statins mainly include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin. The mechanism of action of statins is roughly the same, but due to the difference in chemical structure, there are great differences in the degree of cholesterol lowering.
01. Lovastatin
It is a natural HMG-CoA reductase inhibitor, but due to the lactone structure in the molecule, no HMG-CoA reductase inhibitory effect in vitro, need to enter In vivo, the hydroxylactone structure in the molecule was hydrolyzed to 3,5-dihydroxyvaleric acid before it showed activity.
3,5-dihydroxyvaleric acid and its key pharmacophore decalin ring, there is an ethyl link chain, lovastatin has 8 chiral centers, if the chiral center is changed configuration will lead to a decrease in activity. However, the stereochemistry of the ester side chain on the decalin ring has little effect on the activity.
Clinical application: Lovastatin can competitively inhibit HMG-GoA reductase with high selectivity, can significantly reduce LDL levels, and can increase plasma HDL levels . It is clinically used for the treatment of hypercholesterolemia and mixed hyperlipidemia, and can also be used for the prevention and treatment of ischemic stroke.
02. XinVastatin
It is a drug modified on the side chain of lovastatin decahydronaphthalene ring, the only difference is that there is an additional methyl substituent on the side chain of the decalin ring, making it The lipophilicity was slightly improved, so simvastatin was slightly more active than lovastatin.
Clinical application: for the treatment of hypercholesterolemia and mixed hyperlipidemia, and also for the prevention and treatment of coronary heart disease and ischemic stroke.
03. PravaStatins
It is obtained by opening the lactone ring to 3,5-dihydroxyvaleric acid on the basis of lovastatin, and replacing the methyl group at the 3-position of the decalin ring with a hydroxyl group. Drug. Pravastatin has greater hydrophilicity than lovastatin, and the advantage of this increased hydrophilicity is that it reduces the entry of drugs into lipophilic cells and has better selectivity for liver tissue.
Clinical application: For the treatment of hyperlipidemia and familial hypercholesterolemia.
04. FluorineVastatin
It is the first statin drug obtained by total synthesis. The bicyclic ring in the lovastatin molecule is replaced with an indole ring, and the lactone ring is opened to form a salt with sodium to obtain fluvastatin. Sodium statin. Fluvastatinhas good water solubility, rapid and complete oral absorption, and high protein binding rate.
Clinical application: In addition to its potent hypolipidemic effect, fluvastatin also has the potential to resist arteriosclerosis and reduce the morbidity and mortality of coronary heart disease.
05. AtorvaStatins
is a fully synthetic HMG-CoA reductase inhibitor, with a pyrrole ring to replace the bicyclic ring in the lovastatin molecule, with a ring-opened dihydroxyvaleric acid side chain. It has the characteristics of high water solubility, low lipid solubility, short plasma half-life, rapid and complete oral absorption.
Atorvastatin reduces de novo cholesterol synthesis by inhibiting HMG-CoA reductase and increases the expression of LDL receptors in hepatocytes, thereby increasing the uptake of low-density lipoprotein by hepatocytes and broken down, lowering the amount of LDL in the blood.
Like other statins, atorvastatin reduces triglycerides in the blood and slightly increases the amount of HDL cholesterol.
Clinical application: It is used for various types of hypercholesterolemia and mixed hyperlipidemia; it can also be used for the prevention and treatment of coronary heart disease and stroke. Atorvastatin can reduce the overall mortality of cardiovascular disease, and is also suitable for unstable angina after myocardial infarction and after revascularization.
06. RosolVastatin
is a fully synthetic statin drug whose bicyclic part of the molecule is changed to a polysubstituted pyrimidine ring. Compared with other statins, rosuvastatin has a polar sulfonamide methyl group in its structure, so it has relatively stronger hydrophilicity, Its high selectivity is taken up by hepatocytes and is not easy to enter into other tissue cells, and the effect of inhibiting reductase is stronger.
Clinical application: It is suitable for primary hypercholesterolemia or mixed dyslipidemia whose dyslipidemia cannot be properly controlled by dietary control and other non-drug treatments .
07. PitavaStatins
Molecular structure contains quinoline ring, cyclopropyl and fluorophenyl groups. Based on its unique cyclopropyl structure, pitavastatin can interact with HMG-CoAThe hydrophobic group of the reductase is better chimeric and thus inhibits the enzyme more strongly, while the cyclopropyl group is the basic structure that can protect it from cytochrome P450 enzyme (CYP) metabolism.
Clinical application: It has a clear lipid-lowering effect in patients with hypertension, metabolic syndrome and coronary heart disease. Commonly used for hypercholesterolemia, familial hypercholesterolemia and so on.
Planning: ly
The source of the title map: Zhanku Hailuo
This article was first published on the professional platform of Lilac Garden: Cardiovascular Time
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