Jan. 19 - Med Chem - Antihyperlipidemic agents (1).pdf

Cardio/Renal Systems II Anti-hyperlipidemic agents Dr. Sabesan Yoganathan SAH-330 / [email protected] PHR 4111 Acknowledgement: Part of lecture is from Dr. Zito’s presentation PHR 4111- Cardio/Renal PHR 4111 - Drugs and Diseases of the Cardiovascular Systems (Medicinal Chemistry Section) Dr. Sabe...

Cardio/Renal Systems II Anti-hyperlipidemic agents Dr. Sabesan Yoganathan SAH-330 / [email protected] PHR 4111 Acknowledgement: Part of lecture is from Dr. Zito’s presentation PHR 4111- Cardio/Renal PHR 4111 - Drugs and Diseases of the Cardiovascular Systems (Medicinal Chemistry Section) Dr. Sabesan Yoganathan | [email protected] (best way to contact) Office: St. Albert’s Hall 330 Office hours: F – 4:30 – 6:00 pm (by appointment) I. II. III. IV. V. Hyperlipidemia Ischemic heart disease Acute coronary syndrome Arrhythmias Cardiovascular emergencies Dr. Sabesan Yoganathan 2 PHR 4111- Cardio/Renal PHR 4111 - Drugs and Diseases of the Cardiovascular Systems (Medicinal Chemistry Section) Textbook: Foye’s Principles of Medicinal Chemistry, 7th Ed. Lemke, T. L.; Williams, D. A.; Roche, V. F.; Zito, S. W. 2012, Eds. Williams and Wilkins. Foye’s Principles of Medicinal Chemistry, 8th Ed. Roche, V. F.; Zito, S. W.; Lemke, T. L.; Williams, D. A. 2019, Eds. Williams and Wilkins. I. II. Chapter 21 – Anti-arrhythmic agents Chapter 21 and Chapter 23 – Nitrates and calcium channel blockers III. Chapter 25 – Antihyperlipidemic drugs IV. Chapter 26 – Antiplatelet drugs Dr. Sabesan Yoganathan 3 Cardiovascular Diseases NCDs = non-communicable diseases Dr. Sabesan Yoganathan 4 Hyperlipidemia Hyperlipidemia is an indicator of susceptibility to Coronary Heart Disease (CHD) or Coronary Artery Disease (CAD) Defined: Elevated plasma levels of Lipids – Triglycerides and Cholesterol Triglycerides are long chain fatty acid esters of glycerol Triglycerides are stored in adipose tissue and are hydrolyzed by lipases to free fatty acids (FFAs) when needed for energy – Found in plasma combined with lipoproteins: VLDL, HDL, LDL and Chylomicrons Triglycerides transported primarily by VLDLs and Chylomicrons Cholesterol found in varying amounts in all lipoproteins Dr. Sabesan Yoganathan 5 Cholesterol lipoproteins serve as carriers for cholesterol due to its high lipophilicity Dr. Sabesan Yoganathan 6 Cholesterol LDL = low density of proteins to lipids ~> unstable and easily oxidized HDL = high density of proteins to lipids 7 Dr. Sabesan Yoganathan Cholesterol Biosynthesis pharmacophore of HMG-CoA reductase inhibitors mimics HMG-CoA or mevalonic acid know this step - key step in blocking cholesterol synthesis via HMG-CoA reductase inhibitors Full name of HMG-CoA Dr. Sabesan Yoganathan 8 Cholesterol Biosynthesis Dr. Sabesan Yoganathan 9 Cholesterol Derivatives vitamin D too Dr. Sabesan Yoganathan 10 Treatment Options Primary problem lipid in CHD is believed to be Cholesterol – Diet ~300 mg/day, Biosynthesized ~1 gm/day – Controlling diet alone may not be beneficial for many patients. Therapeutic approaches to treatment of hyperlipidemia: – Inhibiting intestinal reabsorption of bile acids (bile acid sequestering agents) do not reabsorb the bile acid that is required for lipid digestion – Inhibiting triglyceride biosynthesis and VLDL formation (niacin) – Inhibiting dietary absorption of cholesterol (ezetimibe) – Stimulating triglyceride cleavage and clearance (fibrates) – Inhibiting cholesterol biosynthesis (3-hydroxy-3methylglutaryl CoA reductase inhibitors: HMGR; statins) – LDL-cholesterol reducers (PCSK9 inhibitors) Dr. Sabesan Yoganathan 11 Lipid-lowering Agents Chemical classes – Bile sequestering agents – Niacin (not as commonly recommended anymore, but still helpful) – Fibric Acids – Statins – HMG-CoA reductase inhibitors – Cholesterol Absorption Inhibitors – LDL-cholesterol reducers (PCKL9 antibody) Dr. Sabesan Yoganathan 12 Bile Sequestrants traps bile acids in the gut and facilitates its excretion Anion-exchange resins; they are water insoluble; inert to digestive Be able to identify the type of amine present in each bile sequestrant enzymes and not absorbed so you can identify the type of bile acid it binds to - bile acids: acidic/anionic ~> trap with resin that's basic/cationic Cholestyramine is a copolymer of polystyrene and divinylbenzene containing ~4 meq of quaternary ammonium groups/gram. Quaternary ammonium: N with 4 groups attached and (+) charge One gram resin binds ~ 2 grams of bile acids Colestipol is a copolymer of diethylenetriamine and 1-chloro-2,3epoxypropane. Functional groups are tertiary amines Tertiary amine: N with 3 groups attached and no charge Binds < 2 grams of bile acids/gm….depends upon pH of the intestinal tract. Colesevelam is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)trimethylammonium bromide. Dr. Sabesan Yoganathan 13 Bile Acids pink: sulfonic acid Sirc and coworkers. Eur. J. Med. Chem., 2018, 144, 300. Dr. Sabesan Yoganathan 14 drug interactions occur more severely with active forms of statins containing -COOH (if administered with a prodrug form of statin, it would have less drug effects since it won't bind to it) Bile Sequestrants H C CH2 H C N CH2 CH2CH2 CH2 HC OH CH2 H2C CH H2C cholestyramine N(CH 3)3 N n N H2 C HC OH colestipol colestipol requires an acidic environment to gain a positive charge to be a bile sequestrant and bind to carboxylate anion H C H C H2 C CH2 N CH2CH2 H C H2 C (CH 2)6N(CH3)3 colesevelam the group that it binds to usually has acidic groups (mainly -COOH, sulfonic acid, sulfonamide) Cl- anion exchanged for carboxylate anion "anionic exchange" Dr. Sabesan Yoganathan 15 Bile Sequestrants MOA: – Bind bile salts in the intestinal tract thereby reducing their reabsorption (active) and increasing their excretion in the feces – Liver compensates by increasing de novo synthesis of bile salts from cholesterol necessitating an increase in liver cholesterol synthesis – Increased liver synthesis of cholesterol also increases hepatic LDL-receptor synthesis. – Bottom line: decreased plasma cholesterol and LDL’s Dr. Sabesan Yoganathan 16 Bile Sequestrants Drug Interactions (generally – anion-exchange resins will tend to bind anionic drugs, i.e. acidic drugs: – NSAIDS, Anticoagulants, Valproic acid, Furosemide, Sulfonylureas, Troglitizone, HMG-CoA reductase Inhibitors Also decreases absorption of certain drugs by non-specific binding: – Digoxin, Tricyclic antidepressants, Thiazide diuretics, Benzodiazepines, Corticosteroids, b-Blockers Recommend taking most drugs 2 hours apart from cholestyramine or colestipol Dr. Sabesan Yoganathan 17 Niacin O Niacin, named changed from nicotinic acid because it sounds similar to the poison – nicotine Aka Vit B3 N Biosynthesized from tryptophan Found in NAD/NADP as a co-enzyme necessary for dehydrogenase reactions. Deficiency of niacin or tryptophan causes pellegra High doses lower triglycerides and cholesterol. VLDL and LDL are reduced but HDLs are increased. Nicotinamide is not active this way. MOA (various) – Inhibit lipolysis of stored triglycerides in adipose tissue resulting in decreasing FFA, VLDLs and LDLs in plasma – Decreases liver triglyceride esterification by diacylglycerol acyltransferase (DAGAT) reducing VLDL particle size – Increases lipoprotein lipase activity hydrolyzing triglycerides in VLDLs hydrolysis of VLDL Leads to clearance of VLDL and increase in formation of HDL – Must be anionic to be an effective antihyperlididemic Dr. Sabesan Yoganathan OH 18 Niacin NiacMajor side effects: flushing and GI distress Extended release formulations can significantly reduce flushing Drug-Drug Interactions: With statins can increase myotoxicity including rhabdomyolysis With anticoagulants can prolong bleeding time O O niacin glycine OH N H COOH nicotinuric acid N O phase 2 conjugation converts active niacin into metabolite N Niacin ( Nicotinic acid, vit. B3) Metabolism OH NH2 N N N N-methylnaicin O CH3 NH2 N O N O O H OH H H P OH O P CH2O OH N O H H OH OH H H OH O NAD H Dr. Sabesan Yoganathan 19 Fibric Acids Derivatives of Fibric Acid (Phenoxyisobutyric acids) Where R can be nothing or a propyl group impacts oral absorption Where R1 can be lipophilic substituent active drug = free carboxylic acid Where R2 can be H (acid) or small alkyl group (esters) toto be be prodrug = alkyl group, forming ester – Must be anionic for activity; esters are pro-drugs Name comes from the chemical name of the active anionic form; Phoxyisobutyrate (phibrate = fibrate). a short aliphatic group such as Dr. Sabesan Yoganathan 20 Fibric Acids CH3 O Cl C O C CH3 COO CH(CH3 )2 prodrug bc R2 is a small alkyl group, creating an ester Fenofibrate (Trecor) R1= p-Cl benzoyl , R2 = isopropylgroup A Pro-drug, metabolized to active free acid; excreted as the glucuronide phase II glucuronidation MOA – Activates peroxisome proliferator-activated receptor alpha (PPARa) stimulating lipoprotein lipase expression resulting in: Triglyceride cleavage from VLDLs facilitating VLDL clearance and resulting in HDL increase Increased FFA oxidation and inhibition of triglyceride synthesis – Also facilitates cholesterol removal from liver. May cause gall stones remove cholesterol by converting to bile acid but too much bile acid can cause gallstone formation – Fenofibrate/simvastatin combo has been shown to reduce diabetic retinopathy progression DI’s: Highly protein bound; displaces anticoagulants and sulfonylureas 21 DIs with other highly protein bound drugs since fibrates are very highly protein bound Dr. Sabesan Yoganathan Fibric Acids Question: What functionality makes it a prodrug vs. active drug? Is gemfibrozil or fenofibrate an active drug? - R2 = ester (prodrug) vs. R2 = H (active) R1= H, R2 = H, R = propyl group; o & m- methyl groups Administered as the active free acid with good oral absorption MOA – PPARa agonist enhances lipoprotein lipase DI’s: – Highly protein bound; displaces anticoagulants and sulfonylureas – May cause increased risk of cholithiasis (gall stones) when coadministered with ezetimibe DIs: Risk of myopathy when given with statins; should be avoided in patients with hepatic/renal dysfunction Dr. Sabesan Yoganathan 22 Fibric Acids Dr. Sabesan Yoganathan 23 Statins The “Statins” decrease cholesterol by inhibiting the rate limiting step of its biosynthesis: hydroxymethyl glutaryl CoA reductase (HMGR) HMGR is the enzyme that converts HMG-CoA to Mevalonic acid Being a reductase it requires NADPH as a co-enzyme and a source of electrons in the form of a ‘hydride’ HMGR is a membrane-bound enzyme consisting of 4 units (tetramer) and each unit consists of 3 domains: – N-domain is the N-terminal and is embedded in the membrane of the endoplasmic reticulum – L-domain is the Largest domain and contains the catalytic site that binds HMG-CoA – S-domain is the Smallest unit and is connected to the Ldomain via a small loop of protein called the cis loop. The Sdomain contains the binding site for the co-enzyme, NADPH. Dr. Sabesan Yoganathan 24 Biochemical reduction of HMG-CoA Roche, V. F. Am. J. Pharm. Ed., 2005, 69, 546. Dr. Sabesan Yoganathan 25 Binding of HMG-CoA to the enzyme Compare this slide with slide 30 to see how atorvastatin vs. HMG-CoA interacts with HMG-CoA reductase Roche, V. F. Am. J. Pharm. Ed., 2005, 69, 546. Dr. Sabesan Yoganathan 26 Statins Simvastatin, lovastatin: ring cyclization to create lactone ~> prodrug ~> requires hydrolysis by esterase O Top: naturally derived from fungal species Bottom: synthetic Alagona, Jr. P. Core Evidence, 2010, 5, 91-105. Dr. Sabesan Yoganathan 27 Statin SAR The Statins are competitive antagonists of HMGR therefore affinity for the enzyme is an important factor The statins are analogs of mevastatin (desmethyl-lovastatin) isolated from Penicillium citrinum. Lovastatin was first isolated from Monascus ruber and Aspergillus terreus Statin Pharmacophore: – A dihydroxyheptanoic acid (essential for enzyme binding) – A ring system with lipophilic substituents (binds in CoA-SH area and accounts for high affinity: 103 to 104 times higher than HMG-CoA itself) Dr. Sabesan Yoganathan 28 Statin SAR The Ring Systems of the statins include the following: H N H N N N N Hexhydronaphthalene lovastatin, simvastatin, pravastatin Pyrrole atorvastatin Indole fluvastatin Quinoline pitavastatin Pyrimidine rosuvastatin At least 2 lipophilic groups found on the rings: – Statins with hexahydronapthylene all have one or two CH3’s and one methylbutyrate ester – Statins which have a nitrogen heterocycle all have isopropyl and p-fluorophenyl substituents H3C H2C CH3 O C C H methylbutyrate CH3 O F CH CH3 isopropyl p-fluorophenyl Dr. Sabesan Yoganathan 29 Statin Metabolism Amides and sulfonamides are isosteres (similar chemical nature) Question: Identify the type of interaction with the particular functional group. What type of residue (acidic, basic, polar, nonpolar) and its usual interaction? - carboxylic = ionic interaction - hydroxyl = hydrogen binding interaction Sulfonamide side chain of rosuvastatin also forms a H-bond with Ser565. hydrogen binding with -OH and amide group of atorvastatin understand how atorvastatin interacts Roche, V. F. Am. J. Pharm. Ed., 2005, 69, 546. Dr. Sabesan Yoganathan 30 Statin Metabolism The Statin pro-drugs contain a lactone ring and must be hydrolyzed by esterases to active acid metabolites (lovastatin and simvastatin) The Statins are metabolized by CYP3A4 and 2C9 – 3A4 metabolizes lovastatin, simvastatin and atorvastatin – 2C9 metabolizes fluvastatin – Naringin in grapefruit juice inhibits CYP450 isoforms (3A4) – Pravastatin is resistant to CYP3A4 but is oxidized in the gut/liver. It is 65% excreted unchanged. Dr. Sabesan Yoganathan 31 Statin Metabolism Roche, V. F. Am. J. Pharm. Ed., 2005, 69, 546. Dr. Sabesan Yoganathan 32 Statin Metabolism Roche, V. F. Am. J. Pharm. Ed., 2005, 69, 546. Dr. Sabesan Yoganathan 33 Statin Metabolism metabolism usually either on ring structure or side chain Roche, V. F. Am. J. Pharm. Ed., 2005, 69, 546. Dr. Sabesan Yoganathan 34 Statin Metabolism pravastatin and rosuvastatin are quite hydrophilic Lipophilicity is important for the transport of the drug molecule into the liver - lipophilic groups can be passively transported across barriers - hydrophilic drugs require organic anionic transporter (OAT) - reduces chances of non-target effects - increase selectivity Alagona, Jr. P. Core Evidence, 2010, 5, 91-105. Dr. Sabesan Yoganathan 35 Cholesterol Absorption Inhibitors Introduction same as beta-lactam – CAI’s are a class of 2-azetidinone derivatives originally developed as a acyl-coenzymeA:cholesterol acyltransferase (ACAT) inhibitors R3 R1 N R2 O 2-azetidinone – They reduce plasma cholesterol levels by suppressing absorption of dietary cholesterol and by suppressing the assembly and secretion of apolipoprotein B-containing lipoproteins (VLDL in the liver and chylomicrons in intestine). – They reduce total-C, LDL-C and triglycerides (TG), and increase HDL-C in patients with hypercholesterolemia – Used alone or in combination therapy with HMG-CoA reductase inhibitors (Statins) Dr. Sabesan Yoganathan 36 Cholesterol Absorption Inhibitor – SAR - Mainly to protect from metabolic lability – One example to date: Ezetimibe (Zetia): F HO 4 1 N 3 2 F O Ezetimibe (Zetia) OH – Key structural features of activity: The 1,4-diaryl-b-lactam structure is important to activity N(1)-aryl substituent protected at 4’ position (F) (4S)-aryloxy substituent (either –OR or OH). This is glucuronidated to an active metabolite The benzylic hydroxylation of the C(3)-side chain is stereochemically important where the S-isomer is 5-fold more potent than the R-isomer The phenolic and alcoholic hydroxyls keep it localized in the intestines Dr. Sabesan Yoganathan 37 Ezetimibe Metabolism Dr. Sabesan Yoganathan 38 PCSK9 Antibody PCSK9 antibodies decrease LDL-C by increasing the recycling of the LDL-receptor primarily on hepatocytes. This leads to a more efficient removal of LDL-C from circulation. PCSK9 is Proprotein Convertase Subtlisin/Kexin type. – It acts by reducing the amount of LDL-receptors – It is a serine protease synthesized in the liver as pro-PCSK9 which is metabolized to the active enzyme in the endoplasmic reticulum. – It binds in a one-to-one stoichiometry to the LDL-receptor and together with LDL-C particles enters the cell and enhances the breakdown of both the LDL-C and the LDL-receptor Blocking PCSK9 results in increased availability of the LDLReceptor to remove LDL-C from the circulation PCSK9 inhibitors are approved for the treatment of Familial hypercholesterolemia and for patients who cannot control LDLcholesterol with statins alone. Dr. Sabesan Yoganathan 39 PCSK9 Antibody Normally, LDL particle pairs with PCSK9 in order to be internalized by LDL receptor. Then, everything is degraded, including LDL receptor. Drug: antibody that targets PCSK9 protein prevents it from complexing with LDL particle. Therefore, the LDL particle is internalized itself, and LDL receptor is returned to the cell surface, permitting more LDL receptors for LDL uptake PCSK9-mediated degradation of LDLR. A complex of LDL-C, LDLR, and PCSK9 is internalized into hepatocytes into clathrin-coated pits and subsequently undergoes lysosomal degradation. Ciccone et al. Pharmacol. Res. 2015, 102, 168-175. Dr. Sabesan Yoganathan 40 PCSK9 Antibody PCSK-mAb bound to PCSK9 prevent the association between PCSK9 and the LDLR. The LDLR binds the LDL particle and is internalized, and then the LDL particle is degraded in the lysosome, whereas the LDLR is recycled back to the plasma membrane. Ciccone et al. Pharmacol. Res. 2015, 102, 168-175. Dr. Sabesan Yoganathan 41 PCSK9 Antibody Alirocumab ( Praluent) – Approved in 2015 contingent on completion of further clinical trials to determine safety and efficacy. it cost ~ $14,000 per year! – Alirocumab is a human IgG1 mAb produced in Chinese Hamster Ovary cells by recombinant DNA technology – Chemistry: consists of two disulfide-linked human heavy chains, each covalently linked to a human light chain. The variable domains of the heavy and light chains combine to form the PCSK9 binding site. Alirocumab has an approximate molecular weight of 146 kDa. – SEs: Difficulty with breathing or swallowing, fever, hives, nausea, reddening of the skin, especially around the ears, swelling of the eyes, face, or inside of the nose and unusual tiredness or weakness – Metabolism: like all Immunoglobulins in the endoplasmic reticulum to component amino acids Dr. Sabesan Yoganathan 42 PCSK9 Antibody Evolocumab (Repatha) Also approved in 2015 with same requirement as alirocumab. Evolcumab is a human monoclonal immunoglobulin G2 (IgG2) with an approximate molecular weight (MW) of 144 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells SEs: Injection site erythema and pain, allergic reacts (rash, eczema and uticaria), back pain, and upper respiratory tract infection PK: – Adsorption SQ medium peak in 3-4 days, bioavailability is 72% – Metabolism, proteolytic degradation via endoplasmic reticulum Dr. Sabesan Yoganathan 43 Summary Sites of action of antihyperlipidemic agents Citation: Agents Used in Dyslipidemia, Katzung BG. Basic & Clinical Pharmacology, 14e; 2017. 44