Pharmaceutical Chemistry III, Lecture 3
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Questions and Answers

What is the primary focus of Structure-Activity Relationship (SAR) in the context of ACE inhibitors, AT1 antagonists, and Renin inhibitors?

  • The synthesis techniques employed in drug manufacturing
  • The economic impact of these drugs in the pharmaceutical industry
  • The physical characteristics of the drug molecules
  • The correlation between pharmacophoric features and their biological activity (correct)

Which of the following best describes the relationship between ACE inhibitors' chemical structures and their pharmacological actions?

  • The active compounds act independently of their chemical structure
  • Only the molecular weight determines pharmacological action
  • There is no significant correlation between structure and activity
  • The physicochemical properties influence their therapeutic efficacy (correct)

In the context of drug design, what is the main distinction between structure-based and ligand-based principles?

  • Ligand-based relies on existing knowledge of receptor binding (correct)
  • Structure-based does not consider chemical properties
  • Ligand-based is exclusively theoretical with no application
  • Structure-based focuses solely on the environment of the drug

What role does the metabolism of ACE inhibitors play in their therapeutic use?

<p>It determines the dosage regimen and potential side effects (B)</p> Signup and view all the answers

Which of the following is NOT typically a therapeutic use of ACE inhibitors?

<p>Anxiety alleviation (B)</p> Signup and view all the answers

How do the pharmacological basics of therapeutics enhance the use of ACE inhibitors in medical practice?

<p>By enabling tailored treatment plans based on patient-specific factors (B)</p> Signup and view all the answers

What should be considered when evaluating the activity versus side effects of ACE inhibitors?

<p>The chemical features of the drug and patient response (B)</p> Signup and view all the answers

Which of the following techniques is essential for the synthesis and analysis of ACE inhibitors?

<p>Analytical chemistry techniques (A)</p> Signup and view all the answers

What is a common side effect associated with ACE inhibitors?

<p>Metallic taste (C)</p> Signup and view all the answers

Which ACE inhibitor is known to be the most liable to metabolism into its disulfide product?

<p>Benazepril (A)</p> Signup and view all the answers

What is the significance of CADD in the context of angiotensin receptor blockers?

<p>It helps in optimizing the structure for better binding. (C)</p> Signup and view all the answers

Which group of compounds do most angiotensin receptor blockers belong to?

<p>Biphenylterazol derivatives (D)</p> Signup and view all the answers

In the assay of captopril, what technique is used to determine the end point?

<p>Direct titration with iodine (B)</p> Signup and view all the answers

What is the effect of the extension of phenyl in the discovery of Losartan?

<p>Improves binding properties. (D)</p> Signup and view all the answers

Which functional group is part of the structure of many angiotensin II receptor blockers?

<p>Tetrazole (D)</p> Signup and view all the answers

Which side effect is specifically related to excessive bradykinin when taking ACE inhibitors?

<p>Dry cough (A)</p> Signup and view all the answers

What is the primary yield percentage mentioned for the synthesis process?

<p>32% (A)</p> Signup and view all the answers

Which chemical compound is used as a reagent in the synthesis process alongside NaOH?

<p>Br (A)</p> Signup and view all the answers

Which of the following statements is true regarding the industrial scale application?

<p>It cannot be applied on industrial scale. (C)</p> Signup and view all the answers

What element is indicated to have a potential issue during synthesis based on the content details?

<p>Chlorine (A)</p> Signup and view all the answers

Which compound has a higher activity against ACE compared to Succinyl-L-proline?

<p>Captopril (D)</p> Signup and view all the answers

What modification does 3-Mercaptopropanoyl-L-proline feature compared to Succinyl-L-proline?

<p>Replacement of -COOH with -SH (A)</p> Signup and view all the answers

Which structural feature is commonly associated with synthetic pathways in the outlined synthesis?

<p>Functional groups with halides (A)</p> Signup and view all the answers

Which of the following ACE inhibitors is classified as a prodrug?

<p>Lisinopril (B)</p> Signup and view all the answers

What role does the phenylbutyroyl moiety serve in ACE inhibitors?

<p>Facilitates interaction with a lipophilic pocket (B)</p> Signup and view all the answers

Which compound is considered the most hydrophilic analogue among ACE inhibitors?

<p>Enalaprilat (B)</p> Signup and view all the answers

What is a characteristic of chiral atoms in ACE inhibitors?

<p>They are of the S configuration (B)</p> Signup and view all the answers

Which of the following is NOT a type of group that can chelate Zinc in ACE inhibitors?

<p>Amino acid containing (C)</p> Signup and view all the answers

How do prodrugs improve pharmacokinetics in ACE inhibitors?

<p>By reducing their zwitterionic nature (A)</p> Signup and view all the answers

What process converts olmesartan medoxomil into its active form?

<p>Hydrolysis (B)</p> Signup and view all the answers

Which of the following statements is true about losartan metabolism?

<p>The active metabolite is formed from oxidation. (A)</p> Signup and view all the answers

What is a key characteristic of losartan in comparison to olmesartan medoxomil?

<p>It has an active metabolite. (C)</p> Signup and view all the answers

Which component is a reactant in the laboratory synthesis of losartan?

<p>4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile (D)</p> Signup and view all the answers

What is a potential drawback of the synthesis of losartan?

<p>Production of multiple regioisomers. (A)</p> Signup and view all the answers

What reagent is mentioned in the synthesis process of losartan?

<p>NaN3 (B)</p> Signup and view all the answers

Why is the reaction time for losartan synthesis noted as long?

<p>The formation of the desired product is slow. (B)</p> Signup and view all the answers

What hazard is associated with the synthesis of losartan?

<p>Explosive inorganic azides. (B)</p> Signup and view all the answers

What is the primary therapeutic indication for the use of ARBs?

<p>Hypertension (D)</p> Signup and view all the answers

Which statement accurately describes a key advantage of AT1 antagonists over ACE inhibitors?

<p>They do not affect bradykinin levels. (B)</p> Signup and view all the answers

What is the composition of Entresto?

<p>A combination of Sacubitril and Valsartan (B)</p> Signup and view all the answers

Which of the following enzymes is primarily inhibited by Sacubitril?

<p>Neprilysin (A)</p> Signup and view all the answers

In relation to cardiac health, what condition is primarily treated with the combination of Sacubitril and Valsartan?

<p>Chronic heart failure (D)</p> Signup and view all the answers

What is the role of neprilysin in the human body?

<p>It cleaves and inactivates several peptide hormones. (A)</p> Signup and view all the answers

Which of the following conditions is a potential use-case for ARBs?

<p>Chronic kidney disease (D)</p> Signup and view all the answers

What is NOT a potential side effect of using AT1 antagonists?

<p>Cough (A)</p> Signup and view all the answers

Flashcards

ACE Inhibitors Metabolism Pathways

Specific metabolic processes ACE inhibitors undergo in the body.

Structure-Based Drug Design

Drug design approach using the 3D structure of a target molecule.

Pharmaceutical Terms/Abbreviations

Proper medical terminology, abbreviations, and symbols in pharmaceutical practice.

ACE Inhibitors Properties

Characteristics (e.g., mechanism of action, uses, dosages, contraindications, drug interactions) of ACE Inhibitors.

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Structure-Activity Relationship (SAR)

Relationship between the chemical structure of a drug and its biological activity.

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Drug Synthesis/Purification

Methods used to create, purify, and identify medicinal compounds.

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Drug Activity vs. Side Effects

Balancing the desired effect of a drug against its potential side effects in treatment.

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Pharmacological Basics (ACE inhibitors, AT1 antagonists, Renin inhibitors)

Using knowledge of drug effects on the body to wisely pick and use ACE inhibitors, AT1 antagonists, and Renin inhibitors, related to specific diseases.

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ACE Inhibitors

Drugs that inhibit the activity of Angiotensin-Converting Enzyme (ACE).

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Succinyl-L-proline

A specific ACE inhibitor with a carboxylate group.

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2-Methylsuccinyl-L-proline

An ACE inhibitor with an additional methyl group.

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3-Mercaptopropanoyl-L-proline

An ACE inhibitor that replaces -COOH with -SH for enhanced binding.

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Captopril

An ACE inhibitor, example of a thiol containing ACE inhibitor.

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Prodrug

Inactive substance that converts to active form in the body.

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Enalaprilat

Active form of enalapril, highly hydrophilic.

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SAR of ACE Inhibitors

Structure-activity relationship of ACE inhibitors. Proline related moiety and Zinc chelation.

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Losartan Synthesis

The process of creating the drug Losartan, an angiotensin II receptor blocker, used for hypertension and heart failure treatment.

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Low Yield Reaction

A chemical reaction that produces a small amount of desired product compared to the starting materials.

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Why is it important to improve the yield?

Higher yield means more efficient production, less waste, and lower cost for manufacturing drugs.

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What is the problem with the Losartan synthesis?

The current synthesis process produces a low yield of Losartan, making it expensive and inefficient to produce on a large scale.

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What is the goal of improving the synthesis?

To find better reaction conditions or a new pathway to produce Losartan with a higher yield, making it more affordable and accessible.

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ACE Inhibitor Side Effects

Common side effects of ACE inhibitors include skin rash, a metallic taste in the mouth, and a dry cough due to increased bradykinin levels.

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ACE Inhibitor Mechanism

ACE inhibitors block the angiotensin-converting enzyme, preventing the conversion of angiotensin I to angiotensin II. This inhibits vasoconstriction and reduces blood pressure.

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Captopril Metabolism

Captopril is metabolized into its disulfide form. Other ACE inhibitors are eliminated as glucuronide conjugates.

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Captopril Assay

Captopril is assayed by direct titration with iodine using potentiometric detection. This method determines the end point and is considered 'stability-indicating.'

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Losartan Discovery

Losartan was discovered through computer-aided drug design (CADD). It initially showed weak antagonistic activity but was optimized by extending the phenyl group.

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Angiotensin II Receptor Blockers (ARBs)

ARBs, also known as sartans, antagonize the angiotensin II receptor (AT1), preventing its vasoconstrictive effects and lowering blood pressure.

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ARBs Structure

Most ARBs are biphenylterazole or biphenylcarboxylic acid derivatives. The tetrazole and carboxylic groups are bio-isosteres, similar in size, acidity, and electronegativity.

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Electrostatic Potential Map

This map shows the distribution of charges on a molecule. Comparing maps for Losartan and Telmisartan helps understand their different interactions with the receptor.

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Olmesartan Medoxomil

A prodrug that needs to be converted to its active form (olmesartan) in the body. This conversion happens through hydrolysis.

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Losartan Metabolism

Losartan is converted into an active metabolite (losartan carboxylic acid) by oxidation of its –CH2OH group to –COOH. It's NOT a prodrug because the original form is also active.

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Active Metabolite

A product of a drug's metabolism that is itself pharmacologically active. It may be a different molecule, but has the same effect as the original drug.

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Regioisomers

Molecules with the same atoms but different arrangements of those atoms, leading to different properties and activity.

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Why is Losartan Synthesis Difficult?

The process involves low yields, the need to purify the desired product, and the use of potentially explosive inorganic azides. It also takes a long time (9 days!) to complete.

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Importance of Purification

In drug synthesis, purifying the desired compound is crucial to remove unwanted byproducts and ensure the drug's safety and effectiveness.

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ARBs

Angiotensin II Receptor Blockers (ARBs) are a class of medications that block the action of angiotensin II, a hormone that constricts blood vessels and raises blood pressure. They are used to treat high blood pressure, heart failure, and other conditions.

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Benefits of ARBs over ACE inhibitors

ARBs are more specific in their action on the AT1 receptor, compared to ACE inhibitors. This results in less or no impact on the bradykinin production, lowering the risk of side effects like cough or angioedema.

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What is Entresto?

Entresto is a combination drug used for treating heart failure, containing Sacubitril (neprilysin inhibitor) and Valsartan (AT1 blocker) in a 1:1 ratio.

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What does Sacubitril do?

Sacubitril is a prodrug that is converted into a dicarboxylic acid derivative. This derivative acts as a neprilysin inhibitor, preventing the breakdown of peptides like ANP and BNP, which have vasodilating effects.

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What is Neprilysin?

Neprilysin is an enzyme that breaks down various peptides, including those that regulate blood pressure and heart function. It is a zinc-dependent metalloprotease.

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How does Entresto work?

Entresto combines the actions of Sacubitril (neprilysin inhibition) and Valsartan (AT1 receptor blockade) to enhance vasodilation and lower blood pressure. This helps improve heart function in patients with heart failure.

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What are some peptides targeted by Neprilysin?

Neprilysin breaks down peptides like glucagon, enkephalins, substance P, neurotensin, oxytocin, bradykinin, ANP, and BNP.

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Why is Entresto important for CHF treatment?

Entresto's combination of Sacubitril (neprilysin inhibition) and Valsartan (AT1 receptor blockade) enhances blood vessel dilation and improves heart function. This targeted approach benefits patients with heart failure.

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Study Notes

Pharmaceutical Chemistry III, Lecture 3

  • The lecture is given by Prof. Dr. Ashraf Abadi
  • The course is PHCMt774
  • By the end of lecture 3, students will be able to demonstrate knowledge of specific pathways of ACE inhibitors, AT1 antagonists, and Renin inhibitors' metabolism.
  • Students will integrate theoretical concepts and methodologies of drug design.
  • Students will use proper pharmaceutical and medical terms, abbreviations, and symbols in practice.
  • Students will articulate knowledge about properties of ACE inhibitors, AT1 antagonists, and Renin inhibitors, including mechanisms, uses, dosages, contraindications, and interactions.
  • Students will show the relationship between properties and chemical structures of these inhibitors.
  • Students will relate physicochemical properties to drug activity.
  • Students will utilize scientific literature to inform professional decisions.
  • Students will correlate essential pharmacophore features to activity and safety/toxicity profiles.
  • Students will select appropriate methods for drug synthesis, purification, and identification.
  • Students will apply pharmacological therapeutics to selecting and using these inhibitors for various diseases.
  • Students will weigh drug activity against side effects in novel medicinal agent design and dosage form suggestions.
  • Students will recognize drug activity and toxicity profiles deduced from structure and metabolism.
  • Students will integrate analytical and synthetic techniques for synthesis and analysis of inhibitors.
  • Students will demonstrate critical thinking, problem-solving, decision-making, and appropriate use of drugs.
  • Students will employ independent learning through exploration of reference materials.

Renin-Angiotensin-Aldosterone System (RAAS)

  • RAAS is a system involving the liver, lungs, and kidneys.
  • It regulates blood pressure and fluid balance.
  • Involves secretion from organs, stimulated and inhibited signals, and active/passive transport.
  • Angiotensinogen is released by the liver, and converted to Angiotensin I.
  • ACE converts Angiotensin I to Angiotensin II.
  • Angiotensin II causes vasoconstriction and increases blood pressure.
  • Aldosterone is released from adrenal glands and causes water and salt retention further increases blood volume.

Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors

  • ACE inhibitors, ARB's, and Renin antagonists are RAAS inhibitors.

Discovery of Captopril

  • Discovered by Miguel Ondetti and David Cushman (BMS)
  • Isolated from snake venom.
  • An efficient antihypertensive agent.
  • A potent ACE inhibitor (non-apeptide).
  • Synthetic analogues failed due to poor oral bioavailability.
  • ACE has structural and physiological properties similar to carboxypeptidase (another enzyme).
  • ACE structurally detaches two amino acids from its substrate; carboxypeptidase removes one.
  • 2-Benzylsuccinic acid is a carboxypeptidase inhibitor, however, not ACE.
  • A model was developed to explore carboxypeptidase inhibition by 2-benzylsuccinic acid.

Captopril Synthesis

  • Preparation of a hybrid dicarboxylic acid derivative including proline and succinic acid.
  • Modifications can enhance ACE activity.

ACE Inhibitors (PRILS)

  • A list of specific ACE inhibitors are mentioned. (Captopril, Lisinopril, Enalapril, Perindopril, Moexipril, Benazepril, Trandolapril, Quinapril, Fosinopril).

SAR of ACE Inhibitors

  • Key characteristics for ACE inhibitors include proline, carboxylate and thiol groups.
  • Captopril and lisinopril are true drugs.
  • Some are pro-drugs (in need of hydrolysis to become active).
  • Enalaprilat is the most hydrophilic analogue typically administrated by injection.
  • Chiral atoms are S configuration to resemble the natural substrate (Angiotensin I).
  • Features of phenylbutyroyl provide for interaction with a lipophilic pocket.

Metabolism and Assay of Captopril

  • Captopril is metabolized into a disulfide product.
  • Other ACEs are excreted as their glucuronide conjugate with the acid function of proline.
  • Benazepril is most liable to metabolism.
  • Captopril assay is done via direct titration with iodine.

Synthesis of Captopril

  • A chemical synthesis process is described, including intermediate steps involving thioacetic acid, methacrylic acid, and various chemical processes.

Synthesis of Enalapril

  • Uses chemical reactions from L-alanine, L-proline, and ethyl 2-oxo-4-phenylbutanoate.
  • A significant portion is about reducing factors.

Angiotensin Receptor Blockers (ARBS, Sartans)

  • Many are biphenylterazole or biphenylcarboxylic acid derivatives.
  • Groups are comparably sized and acidic.
  • Nitrogenous groups (imidazole, benzimidazole, or open chain) are present.
  • Losartan and telmisartan show specific electrostatic potentials.

Metabolism of Sartans

  • Olmesartan medoxomil is a prodrug to olmesartan.
  • Losartan is metabolized by the oxidation from CH2OH to COOH.

Laboratory Synthesis of Losartan

  • Two regioisomers require purification.
  • Explosives and long reaction times are present.
  • A discussion on how to address these challenges for industrial scale.

Uses of ARBs

  • Used in diseases like hypertension, CHF, LVH, LVD, and acute myocardial infarction.
  • Often administered in conjunction with diuretics like hydrochlorothiazide.
  • ARBs are more specific and have a reduced effect on bradykinin production or metabolism. This, in turn, limits side effects like, cough and angioedema.
  • A particular Valsartan worldwide recall incident is noted (August 2018 due to NDMA contamination).

Entresto

  • A combination of Sacubitril and Valsartan. Used for CHF treatment.
  • Sacubitril is a neprilysin inhibitor, whereas Valsartan is an AT1 blocker.
  • Both are administered in a 1:1 mixture.

Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

  • Angiotensin II, Angiotensin I, receptors, and Neprilysin activity.
  • Increased and decreased levels in cases of these components are noted.
  • Neprilysin is a metalloprotease that has a role in deactivating various peptides.

Renin Inhibitors: Aliskiren (Rasilez)

  • Aliskiren enhances affinity and selectivity toward aspartyl peptidases.
  • Discussed using homology modeling and structure-based drug design.
  • It is an example of transition state analogs.
  • Demonstrates chemical reactions to show the process.

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This quiz focuses on Lecture 3 of Pharmaceutical Chemistry III, presented by Prof. Dr. Ashraf Abadi. It covers key concepts related to ACE inhibitors, AT1 antagonists, and Renin inhibitors, including their metabolism, properties, and drug design methodologies. Students will demonstrate their understanding of pharmacological terms and the relationship between chemical structures and drug activity.

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