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1、1Chapter 10 Cardiovascular Agents (II) Drugs Affecting the Cardiac Disease and Plasma Lipids Regulators 21Cardiovascular Diseases(Millions)32Cardiovascular DiseasesPrimary causes of death in 2002:4Drugs Affecting the Cardiac Disease and Plasma Lipids RegulatorsCardiac Glycosides -Adrenoceptor Agonis
2、ts PDE (PhosphoDiEsterase) Inhibitors Antiarrhythmic Drugs Cardiac Agents:Antianginal DrugsPlasma Lipids Regulators354Cardiac Agents A group of drugs that can increase the contractile force of the myocardium. They are used to treat diseases such as CHF (Congestive Heart Failure), atrial fibrillation
3、, etc. 1. Cardiac Glycosides: Glycosides linked to Steroids. Its effect is thought to be due to elevation of Ca2+concentration. Digitoxin as an exampleABCD3-OH from steroid is usually linked to glycosidesAn unusual 5- membered lactone2. -Adrenoceptor Agonists: Dobutamine as an example.66Cardiac Agen
4、ts 3. PDE (phosphodiesterase) inhibitors.NNNNNH2OOHOOPOONNNNNH2OOHOHOPOOOPDEcAMP Active second messengerAMP Inactive second messengerPDE catalyzes the hydrolysis of cAMP and cGMP, two essential messenger molecules in cell signaling pathways . Inhibition of PDEs can increase the levels of cAMP and cG
5、MP.Intracellular levels of cAMP and cGMP control a wide range of processes: cell growth and differentiation, tissue function and ion channels, etc.There are 11 types of PDEs in human (PDE1-PDE11). 77Cardiac Agents 3. PDE (phosphodiesterase) inhibitors 88Cardiac Agents 3. PDE (phosphodiesterase) inhi
6、bitors: PDE-3 inhibitors NNNNNH2OOHOOPOOcAMPStrongest inhibitorWeakest inhibitorH-bond formationLinkerHydrophobic pocketSelectivity between PDE3a/PDE3b910Antiarrhythmic DrugsNormal rhythmArrhythmic condition 1Arrhythmic condition 21. Na+channel blockers (Quinidine) 2. -Adrenoceptor blockers (Propran
7、olol) 3. K+ channel blockers (Sotalol) 4. Ca2+channel blockers (Verapamil)1011Antiarrhythmic DrugsQuinidine pKa1=5.4 pKa2=10.0 F% 80% Plasma Protein Binding 85% T1/26hMetabolism1112Antianginal DrugsNitrates and its mechanism:NitroglycerinIsosorbide dinitrate1213Plasma Lipids Regulators1. Plasma Lipi
8、ds: 胆固醇, 甘油醇, 磷酯.1314Plasma Lipids Regulators1. Plasma Lipids: 胆固醇, 甘油醇, 磷酯.胆固醇在体内的代谢: 1. 形成内源性甾体激素; 2. 形成胆酸和其盐.1415Plasma Lipids Regulators1. Plasma Lipids: 胆固醇, 甘油酯, 磷酯.甘油酯:磷酯:1516Plasma Lipids Regulators2. 脂蛋白: 血脂在血浆中是以与血蛋白结合的形式存在的. 脂蛋白分为: 低密度脂蛋白 (LDL: Low Density Lipoproteins) bad高密度脂蛋白(HDL: Hig
9、h Density Lipoproteins) good1617Plasma Lipids Regulators3. HMG-CoA 还原酶抑制剂: 他汀类药物(Statins) reduce the synthesis of cholesterol in liver1718Plasma Lipids Regulators3. Cholesterol Absorption Inhibitor (CAI): discovery of Ezetimibe. It was initially an effort to find ACAT (acyl-CoA cholesterol acyltrans
10、ferase) inhibitors. ACAT was believed to be needed in cholesterol absorption. Conformational constraint18193. Cholesterol Absorption Inhibitor (CAI): discovery of Ezetimibe.Plasma Lipids RegulatorsSynthetic route for azetidinone analogs:19203. Cholesterol Absorption Inhibitor (CAI): discovery of Eze
11、timibe.Plasma Lipids RegulatorsAzetidinone cholesterol absorption inhibitors do not inhibit ACAT, they must work via a different mechanism, on a different biological target. 20213. Cholesterol Absorption Inhibitor (CAI): discovery of Ezetimibe. With an unknown biological target, in vivo activity ass
12、ay was used as the primary assay. Also, Bile-diverted rat model was used to prove the metabolite is the active compound.Plasma Lipids Regulators14Metabolized compound 14 lowered cholesterol absorption.Intact compound 14 did not lower cholesterol absorption.21223. Cholesterol Absorption Inhibitor (CA
13、I): discovery of Ezetimibe. Active metabolites are identified:Plasma Lipids RegulatorsActive metabolite of 14 identified from the metabolite bile.Other putative metabolites are also assayed Not more active than 14More active than 14Less active than 1422233. Cholesterol Absorption Inhibitor (CAI): di
14、scovery of Ezetimibe. Ezetimibe was discovered and proved by FDA without knowing its biological target. Later evidence showed NPC1L1 protein may be the biological target. NPC1L1 is critical for the uptake of cholesterol by intestinal cells.Plasma Lipids Regulators1423243. Cholesterol Absorption Inhibitor (CAI): discovery of Ezetimibe. Synthesis:Plasma Lipids Regulators2414ACE inhibitorsSynthesis of Captopril: Neucleophilic addition on 1,4-unsaturated carbonylRead Page 524-528 基础有机化学 邢其毅主编25SAR (Structure-Activity Relationship) of Clonidine:Sympatholytic DrugsClonidine5
