Antihyperlipoproteinemics and Inhibitors of Cholesterol Biosynthesis

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1 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 (grotli@chem.gu.se) verview of drug therapy affecting lipoprotein metabolism Bile acid sequestrants MG-CoA reductase inhibitors Ezitamibe Alipogene tiparvovec Evolocumab 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

2 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

3 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 C C 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

4 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

5 SAR of MG-CoA reductase inhibitors Bioactivation of clofibrat + chemical structures of other fibrates 5

6 SAR fibrates Mechanism of action 6

7 icotinic acid Mechanisms of nicotinic acid-induced changes in lipid metabolism 7

8 Ezetimibe, a cholesterol absorption inhibitors Alipogene tiparvovec Alipogene tiparvovec is a gene therapy treatment that compensates for lipoprotein lipase deficiency (LPLD). In July 2012, the European Medicines Agency recommended it for approval, the first recommendation for a gene therapy treatment in either Europe or the United States. 8

Evolocumab uman monoclonal antibody. Evolocumab is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface.

9 Evolocumab uman monoclonal antibody. Evolocumab is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of liver cells to remove LDL-C "bad" cholesterol from the blood. 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 (grotli@chem.gu.se) 9

10 Urine formation TD-/TA-L Diuretics (PCT) Carbonic anhydrase inhibitors 10

Diuretics (PCT) Carbonic Anhydrase Inhibitors C 3 C S S 2 2 C 3 C S S 2 2 C 3 Acetazolamide Methazolamide S Cl Cl S 2 2 2

11 Diuretics (PCT) Carbonic Anhydrase Inhibitors C 3 C S S 2 2 C 3 C S S 2 2 C 3 Acetazolamide Methazolamide S Cl Cl S S S 2 2 Ethoxzolamide Dichlorphenamide C 2 C 3 C 2 C 3 S C S S C S 3 (C 2 ) 3 S S 2 2 Dorzolamide Brinzolamide 11

12 Diuretics (TD-/TA-L) smotic Diuretics Diuretics (TAL) Loop diuretics 12

13 Loop Diuretics (TAL) Cl, CF3, phenoxy, alkoxy, benzyl or benzoyl groups. Essential Must be acidic ( carboxyl Is the best ) Loop Diuretics (TAL) A wide variety of alkyl groups S 3 1 C 2 Bumetanide 13

Diuretics (Early DCT) Thiazide and thiazide-like diuretics Diuretics (Early DCT) SAR C-7 must have an unsubstituted sulfonamide that is directly attached to the aromatic ring; -2 can be subsituted

14 Diuretics (Early DCT) Thiazide and thiazide-like diuretics Diuretics (Early DCT) 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. 14

15 Diuretics (Early DCT) Acidic proton Diuretics (Early DCT) Properties for the Thiazide-like diuretics 15

16 Quinazolinone derivatives Phthalimideine Derivatives 16

17 ew Drugs Cl 2 2 S S Azosemide Cl C 2 S 2 C Piretanide 2 S 2 Tripamide Diuretics (Late DCT) Potassium-sparing diuretics 17

18 Diuretics (Late DCT) Potassium-Sparing Diuretics Diuretics (Late DCT) Potassium-Sparing Diuretics 18

19 Diuretics (Late DCT) Metabolic conversion of spironolactone to canrenone S C 3 Spironolactone Canrenone C Canrenoic acid anion Eplerenone + C 3 C 3 6 -ydroxyeplerenone 6 -Dihydroxyeplerenone (32%) (20.5%) CYP3A4 Eplerenone CYP3A4 C 3 + C 3 C 3 -ydroxyeplerenone (~8%) 3,6 -Dihydroxyeplerenone (~7%) 19

20 Diuretics (Late DCT) Potassium-Sparing Diuretics Diuretics (Late DCT) Amiloride Cl

21 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. 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. 21

22 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? 22

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Antihyperlipoproteinemics and Inhibitors of Cholesterol Biosynthesis

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