1. lactone ring was substituted to bicyclic ring other rings as long as it was lipophilic and contained ethylene bridges 2. 7-substituted-3,5-dihydroxyheptanoic acids

Block 2 - Dyslipidemia Med Chem Flashcards by Hannah Lapos

Know how cholesterol is degraded?

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Know the biosynthesis of TG?

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What are the drugs within the bile acid sequestant class?

Cholestyramine (Qestran, Prevalite)
Colestipol (Colestid)
Colesevelem (Welchol)

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Describe the MOA of bile acid sequestants?

“Selectively” bind the negatively charged bile acids over other anions

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What was Cholestyramine initially developed for?

Pruritus from increased bile acids

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Describe the structure of Questran?

Polymer of styrene and cross linked with divinylbenzene

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Describe the mechanism and treatment target of bile acid sequestrants?

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Why is Questran poorly absorbed and not metabolized very well?

Cholestryamine has decreased bioavailability in plasma
Permanent charged amino decreases absorption
Polymeric and very lipophilic structure

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How does Colestipol different from Cholestryamine?

Colestid posses a more ionizable nitrogen → more bile acid binding per unit

Secondary/Tertiary amines ionized at intestinal pH

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___ of tertiary amine leads to better binding of Colestid?

Methy iodide quaternization

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Describe how Colesevelam fits the SAR of bile acid sequestrates?

Polymeric
0% F
Act in gut (localized)
Changed amine

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What are the ADRs of BA sequestants? How can it be avoided?

Constipation: co-admin with dietary fibers or psyllium laxatives
Worsen hypertriglyceridemia
Should not be coadministered with other drugs (1 hr before or 4 hr after)

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How does BAS induces TG synthesis?

Decreased BA → increased TG for decreased cholesterol → VLDL levels rise → Increase LDL receptors and return VLDL levels to pre-drug levels

A patient with pre-existing hypertriglyceridemia, leads to an increase in triglycerides

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What is the MOA of HMGRI?

Inhibition of HMG-CoA reductase → Reducing biosynthesis of cholesterol → Compensatory increase of HMGCoA reductase and LDL receptors → Increased uptake of LDL → Cholesterol lowering

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Treatment targets of HLD

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How was Mevastatin discovered?

Consisted of Compactin that was a metabolite of Penicillium

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Lovastatin (_____) is ___ more potent than Mevastatin

Mevacor; 2x

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Describe the transition state of HMGCOa Reductase drugs

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Describe HMGRI SAR?

lactone ring was substituted to bicyclic ring other rings as long as it was lipophilic and contained ethylene bridges
7-substituted-3,5-dihydroxyheptanoic acids

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Lovastatin Brand

Mevacor

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Describe the metabolism of Mevacor?

Lovastatin undergoes lactone hydrolysis → Active from → Metabolized to more hydrophilic metabolites 6-OH or 3-OH

Increasing hydrophilicity doesn’t necessarily mean decreased activity

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What HMGRI are prodrugs? Are they activated by esterase?

Lovastatin, Simvastatin

Lactone hydrolysis

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How does Simvastatin differ from Lovastatin?

Additional methyl group

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How does Pravastatin differ from Zocor and Metacor?

Pravachol has No lactone → Not a prodrug

17% F

Lovastatin/simvastatin = 5%

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Pravastatin Brand

Pravachol Natural

Simvastatin Brand

Zocor Natural

Fluvastatin Brand

Lescol Synthetic

Why does Atorvastatin have such long half-life

T1/2: 14-19 hr Non-naphthalene bicyclic HMGRI Synthetic Very bulky and lipophilic

Atorvastatin Brand

Lipitor

How is Lipitor metabolized?

Addition of OH on para or ortho positions Both equiactive (equal activity)

Why does Rosuvastatin have such a long half life?

T1/2: 19-20 Non-naphthalene bicyclic HMGRI Synthetic Bulky, lipophilic, contains a F

Rosuvastatin BRand

Crestor

What is PCSK9?

Protein convertase subtilizing/kexin type 9 that is activated by by proprotein converses to an activated PCSK9 Important for the degradation of LDL-R (normal process for regulation)

What is an examples of PSCK9 Inhibitors?

Alirocumab (Praluent) Evolocumab (Repatha)

What are some of the characteristics of PSCK9 inhibitors?

1. Monoclonal human antibodies 2. Longer half-life (14-18 days) 3. Dosing Q2W

Alirocumab Brand

Praluent

Evolocumab Brand

Repatha

What is ACL?

ATP-citrate lyase that converts citrate to acetyl-coA

Exampels of ACL inhibitors?

BEmpedoic acid (Nexletol)

What are similarities of citrate and NExletol?

Bempedoic acid is a longer chain → prodrug → binds to CoA (Bempedoyl CoA)

What is the MOA of ACAT inhibitors?

Acyl CoA-cholesterol acyltransferase (ACAT) inhibitors 1. inhibits the synthesis of cholesterol esters 2. Inhibits the esterification of cholesterol in intestinal mucosa 3. Less absorption of cholesterol

Example of ACAT inhibitors?

Ezetimibe (Zetia)

Describe the SAR of ACAT inhibitors?

Pharmacophore for cholesterol absorption inhibitors

How does Zetia undergo metabolism?

Looking at Ezetimibe structure describe its PK properties?

1. Crystalline powder 2. Long half-life due to out compete cholesterol

Why is ezetimiebe a last-resort drug?

Thicken arterial walls, unknown mechanisms

What are vibrates?

Compounds that lower plasma cholesterol and total lipid levels

Describe fibrate SAR?

1. Aromatic ring-O-spacer group-isobutyric acid 2. Isobutyric acid (or ester) head group is essential Class: Phenoxyisobutyric acid

What are fibrite examples?`

1. Gemfibrozil (Lopid) 2. Fenofibrate (Tricor, Trilipix)

What are some counseling points when using vibrates?

1. Indicated for hypertriglyceridemia and familial combined HLD 2. Co-administered with other classes 3. Should be take with food to increase absorption

What are example of lipolysis inhibitors?

Nicotinic Acid (Niacin)

What is nicotinic acid?

Derivative of nicotine that reduces cholesterol levels in humans and lowers serum triglycerides

Describe the Niacin MOA?

How does Niacin have such a short half-life and fast onset?

Very small and easily identified by metabolic enzymes

ADRs of Niacin?

1. Cutaneous VD → flushing/pruritus (Niacin flush) 2. Requires titration to prevent ADRs

Is niacin ER good?

1. Concurent use with statins → less carotid thickening 2. Increased risk for stroke 3. Still an ongoing debate

What is ANGPTL3?

1. Enzyme that blocks lipoprotein lipase (LPL) and endothelial lipase (EL) → LPL/EL converts VLDL to VLDL remnants (IDL) and IDL to LDL

What happens if you inhibit ANGPTL3?

Production of more VLDL remnants (IDL) which is cleared by HoFH Shifts the concentration of IDL to lower causing circulating LDL to re-equalibrate to IDL thus less LDL

What are examples of ANGPTL3 inhibitors?

Evinacumab (Evkeeza)

Describe the overall effect of HMG-CoA reductase inhibitor?

Best for LDL control