Antihyperlipoproteinemics and Inhibitors of Cholesterol Biosynthesis Chapter 25, page 815 (Foye s 7th ed) You are expected to read these pages before you come to the lecture Morten Grøtli Department of Chemistry, Medicinal Chemistry Email: (grotli@chem.gu.se) verview of drug therapy affecting lipoprotein metabolism Bile acid sequestrants MG-CoA reductase inhibitors Ezitamibe plasma cholesterole and LDL levels Fibrates iacin Main effect is to stimulate lipoprotein lipase and to increase the clearence of triglycerides plasma levels of both triglycerides and cholesterole 1
Cholesterol and lipid lowering drugs Bile acid sequestrants 2
The conversion of cholesterol Mechanism of action of mevastatin and lovastatin 3 C 3 C 3 C C 3 R Inactive prodrug C 2 MG CoA Reductase S-CoA 3,5-dihydroxy acid in vivo hydrolysis Mevastatin (R = ) Lovastatin (R = C 3 ) 3 C C 2 S-CoA 3 2 1 C 2 4 5 3 C 7 6 3 C 8' 1' C 3 7' 2' R 3' 6' 5' 4' MG CoA Reductase Active form (Mimic) 3 C C 2 MG CoA Intermediate Mevalonic acid 3
The biosynthesis of cholesterole MG-CoA reductase inhibitors 3 C R C 3 3 C C 3 3 C 3 C C 2 a C 3 F C 2 a Lovastatin (R = ) Simvastatin (R = C 3 ) Pravastatin Fluvastatin F C 2 a F C 2 a F C 2 a 3 C S C 3 Atorvastatin Pitavastatin Rosuvastatin 4
SAR of MG-CoA reductase inhibitors Ezetimibe, a cholesterol absorption inhibitors 5
Bioactivation of clofibrat + chemical structures of other fibrates SAR fibrates 6
Mechanism of action icotinic acid 7
Mechanisms of nicotinic acid-induced changes in lipid metabolism Diuretics Chapter 22, page 728 (Foye s 7th ed) You are expected to read these pages before you come to the lecture Morten Grøtli Department of Chemistry, Medicinal Chemistry Email: (grotli@chem.gu.se) 8
Urine formation smotic Diuretics 9
Carbonic Anhydrase Inhibitors Site 1 Diuretics Carbonic anhydrase inhibitors 10
Carbonic Anhydrase Inhibitors C 3 C S S 2 2 Acetazolamide C 3 C S S 2 2 C 3 Methazolamide S Cl Cl S 2 2 2 2 S S 2 2 Ethoxzolamide Dichlorphenamide C 2 C 3 C 2 C 3 S 2 2 3 C S S C S 3 (C 2 ) 3 S S 2 2 Dorzolamide Brinzolamide 11
Site 3 Diuretics Thiazide and thiazide-like diuretics SAR C-7 must have an unsubstituted sulfonamide that is directly attached to the aromatic ring; -2 can be subsituted with a small alkyl group C-6 EW groups increases the activity, ED groupsdecrease activity (Cl or CF3 are the most common groups); 3,4-dihydro derivatives results in a 10x increase in potency compared to the oxidized thiazide ring C-3 can be substituted. The lipophilicity of the C-3 substituent governs potency and duration. 12
Acidic proton Properties for the Thiazide-like Diuretics 13
Quinazolinone derivatives Phthalimideine Derivatives 14
Site 2 Diuretics Loop diuretics Loop Diuretics 15
Loop Diuretics 5 6 4 2 2 S 3 1 C 2 Bumetanide ew Drugs Cl 2 2 S S Azosemide Cl C 2 S 2 C Piretanide 2 S 2 Tripamide 16
Site 4 Diuretics Potassium-sparing diuretics Potassium-Sparing Diuretics 17
Potassium-Sparing Diuretics Potassium-Sparing Diuretics Metabolic conversion of spironolactone to canrenone S C 3 Spironolactone Canrenone C Canrenoic acid anion 18
Eplerenone + C 3 C 3 6 -ydroxyeplerenone (32%) 6 -Dihydroxyeplerenone (20.5%) CYP3A4 Eplerenone CYP3A4 C 3 + C 3 C 3 -ydroxyeplerenone (~8%) 3,6 -Dihydroxyeplerenone (~7%) Potassium-Sparing Diuretics 19
Amiloride Cl 2 2 2 Questions 1 metaboliseras snabbt och fullständigt och ger ett komplext mönster av metaboliter. En av metaboliseringsvägarna för 1 leder till dethioacetylering, varvid dubbeltbindingen mellan C6 och C7 uppkommer. Rita strukturen. Vid hydrolys av laktonet erhålls kanrenoat. Rita kanrenoat (2p) 20
Questions Föreslå trolig farmakologisk effekt av läkemedel 2 Den profylaktiska effekten av 2 på idiopatisk recidiverande njurstenssjukdom har sin grund i att förklara. Ange vilka typer av interaktioner som er aktuella när 2 binder till sitt target. Förklara structur activitet sambandet för läkemedel 2. Questions 3 Ange samtliga sura och basiska grupper i 3. Ange också om de är laddade eller oladdade vid fysiologiskt p (p 7.4) (3p). Förklara verkningsmekanismen för 3. 3 metaboliseras endast till en liten del (ca 10%). De huvudsakliga metaboliterna är? 21