Pharmaceutical Chemistry III, Lecture 3
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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</p> Signup and view all the answers

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

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

    What is a common side effect associated with ACE inhibitors?

    <p>Metallic taste</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</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.</p> Signup and view all the answers

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

    <p>Biphenylterazol derivatives</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</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.</p> Signup and view all the answers

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

    <p>Tetrazole</p> Signup and view all the answers

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

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

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

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

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

    <p>Br</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.</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</p> Signup and view all the answers

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

    <p>Captopril</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</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</p> Signup and view all the answers

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

    <p>Lisinopril</p> Signup and view all the answers

    What role does the phenylbutyroyl moiety serve in ACE inhibitors?

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

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

    <p>Enalaprilat</p> Signup and view all the answers

    What is a characteristic of chiral atoms in ACE inhibitors?

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

    How do prodrugs improve pharmacokinetics in ACE inhibitors?

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

    What process converts olmesartan medoxomil into its active form?

    <p>Hydrolysis</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.</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.</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</p> Signup and view all the answers

    What is a potential drawback of the synthesis of losartan?

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

    What reagent is mentioned in the synthesis process of losartan?

    <p>NaN3</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.</p> Signup and view all the answers

    What hazard is associated with the synthesis of losartan?

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

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

    <p>Hypertension</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.</p> Signup and view all the answers

    What is the composition of Entresto?

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

    Which of the following enzymes is primarily inhibited by Sacubitril?

    <p>Neprilysin</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</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.</p> Signup and view all the answers

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

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

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

    <p>Cough</p> Signup and view all the answers

    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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    Pharmaceutical Chemistry III Lecture 3 PDF

    Description

    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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