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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?
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?
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?
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?
What role does the metabolism of ACE inhibitors play in their therapeutic use?
Which of the following is NOT typically a therapeutic use of ACE inhibitors?
Which of the following is NOT typically a therapeutic use of ACE inhibitors?
How do the pharmacological basics of therapeutics enhance the use of ACE inhibitors in medical practice?
How do the pharmacological basics of therapeutics enhance the use of ACE inhibitors in medical practice?
What should be considered when evaluating the activity versus side effects of ACE inhibitors?
What should be considered when evaluating the activity versus side effects of ACE inhibitors?
Which of the following techniques is essential for the synthesis and analysis of ACE inhibitors?
Which of the following techniques is essential for the synthesis and analysis of ACE inhibitors?
What is a common side effect associated with ACE inhibitors?
What is a common side effect associated with ACE inhibitors?
Which ACE inhibitor is known to be the most liable to metabolism into its disulfide product?
Which ACE inhibitor is known to be the most liable to metabolism into its disulfide product?
What is the significance of CADD in the context of angiotensin receptor blockers?
What is the significance of CADD in the context of angiotensin receptor blockers?
Which group of compounds do most angiotensin receptor blockers belong to?
Which group of compounds do most angiotensin receptor blockers belong to?
In the assay of captopril, what technique is used to determine the end point?
In the assay of captopril, what technique is used to determine the end point?
What is the effect of the extension of phenyl in the discovery of Losartan?
What is the effect of the extension of phenyl in the discovery of Losartan?
Which functional group is part of the structure of many angiotensin II receptor blockers?
Which functional group is part of the structure of many angiotensin II receptor blockers?
Which side effect is specifically related to excessive bradykinin when taking ACE inhibitors?
Which side effect is specifically related to excessive bradykinin when taking ACE inhibitors?
What is the primary yield percentage mentioned for the synthesis process?
What is the primary yield percentage mentioned for the synthesis process?
Which chemical compound is used as a reagent in the synthesis process alongside NaOH?
Which chemical compound is used as a reagent in the synthesis process alongside NaOH?
Which of the following statements is true regarding the industrial scale application?
Which of the following statements is true regarding the industrial scale application?
What element is indicated to have a potential issue during synthesis based on the content details?
What element is indicated to have a potential issue during synthesis based on the content details?
Which compound has a higher activity against ACE compared to Succinyl-L-proline?
Which compound has a higher activity against ACE compared to Succinyl-L-proline?
What modification does 3-Mercaptopropanoyl-L-proline feature compared to Succinyl-L-proline?
What modification does 3-Mercaptopropanoyl-L-proline feature compared to Succinyl-L-proline?
Which structural feature is commonly associated with synthetic pathways in the outlined synthesis?
Which structural feature is commonly associated with synthetic pathways in the outlined synthesis?
Which of the following ACE inhibitors is classified as a prodrug?
Which of the following ACE inhibitors is classified as a prodrug?
What role does the phenylbutyroyl moiety serve in ACE inhibitors?
What role does the phenylbutyroyl moiety serve in ACE inhibitors?
Which compound is considered the most hydrophilic analogue among ACE inhibitors?
Which compound is considered the most hydrophilic analogue among ACE inhibitors?
What is a characteristic of chiral atoms in ACE inhibitors?
What is a characteristic of chiral atoms in ACE inhibitors?
Which of the following is NOT a type of group that can chelate Zinc in ACE inhibitors?
Which of the following is NOT a type of group that can chelate Zinc in ACE inhibitors?
How do prodrugs improve pharmacokinetics in ACE inhibitors?
How do prodrugs improve pharmacokinetics in ACE inhibitors?
What process converts olmesartan medoxomil into its active form?
What process converts olmesartan medoxomil into its active form?
Which of the following statements is true about losartan metabolism?
Which of the following statements is true about losartan metabolism?
What is a key characteristic of losartan in comparison to olmesartan medoxomil?
What is a key characteristic of losartan in comparison to olmesartan medoxomil?
Which component is a reactant in the laboratory synthesis of losartan?
Which component is a reactant in the laboratory synthesis of losartan?
What is a potential drawback of the synthesis of losartan?
What is a potential drawback of the synthesis of losartan?
What reagent is mentioned in the synthesis process of losartan?
What reagent is mentioned in the synthesis process of losartan?
Why is the reaction time for losartan synthesis noted as long?
Why is the reaction time for losartan synthesis noted as long?
What hazard is associated with the synthesis of losartan?
What hazard is associated with the synthesis of losartan?
What is the primary therapeutic indication for the use of ARBs?
What is the primary therapeutic indication for the use of ARBs?
Which statement accurately describes a key advantage of AT1 antagonists over ACE inhibitors?
Which statement accurately describes a key advantage of AT1 antagonists over ACE inhibitors?
What is the composition of Entresto?
What is the composition of Entresto?
Which of the following enzymes is primarily inhibited by Sacubitril?
Which of the following enzymes is primarily inhibited by Sacubitril?
In relation to cardiac health, what condition is primarily treated with the combination of Sacubitril and Valsartan?
In relation to cardiac health, what condition is primarily treated with the combination of Sacubitril and Valsartan?
What is the role of neprilysin in the human body?
What is the role of neprilysin in the human body?
Which of the following conditions is a potential use-case for ARBs?
Which of the following conditions is a potential use-case for ARBs?
What is NOT a potential side effect of using AT1 antagonists?
What is NOT a potential side effect of using AT1 antagonists?
Flashcards
ACE Inhibitors Metabolism Pathways
ACE Inhibitors Metabolism Pathways
Specific metabolic processes ACE inhibitors undergo in the body.
Structure-Based Drug Design
Structure-Based Drug Design
Drug design approach using the 3D structure of a target molecule.
Pharmaceutical Terms/Abbreviations
Pharmaceutical Terms/Abbreviations
Proper medical terminology, abbreviations, and symbols in pharmaceutical practice.
ACE Inhibitors Properties
ACE Inhibitors Properties
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Structure-Activity Relationship (SAR)
Structure-Activity Relationship (SAR)
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Drug Synthesis/Purification
Drug Synthesis/Purification
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Drug Activity vs. Side Effects
Drug Activity vs. Side Effects
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Pharmacological Basics (ACE inhibitors, AT1 antagonists, Renin inhibitors)
Pharmacological Basics (ACE inhibitors, AT1 antagonists, Renin inhibitors)
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ACE Inhibitors
ACE Inhibitors
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Succinyl-L-proline
Succinyl-L-proline
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2-Methylsuccinyl-L-proline
2-Methylsuccinyl-L-proline
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3-Mercaptopropanoyl-L-proline
3-Mercaptopropanoyl-L-proline
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Captopril
Captopril
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Prodrug
Prodrug
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Enalaprilat
Enalaprilat
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SAR of ACE Inhibitors
SAR of ACE Inhibitors
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Losartan Synthesis
Losartan Synthesis
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Low Yield Reaction
Low Yield Reaction
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Why is it important to improve the yield?
Why is it important to improve the yield?
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What is the problem with the Losartan synthesis?
What is the problem with the Losartan synthesis?
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What is the goal of improving the synthesis?
What is the goal of improving the synthesis?
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ACE Inhibitor Side Effects
ACE Inhibitor Side Effects
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ACE Inhibitor Mechanism
ACE Inhibitor Mechanism
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Captopril Metabolism
Captopril Metabolism
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Captopril Assay
Captopril Assay
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Losartan Discovery
Losartan Discovery
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Angiotensin II Receptor Blockers (ARBs)
Angiotensin II Receptor Blockers (ARBs)
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ARBs Structure
ARBs Structure
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Electrostatic Potential Map
Electrostatic Potential Map
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Olmesartan Medoxomil
Olmesartan Medoxomil
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Losartan Metabolism
Losartan Metabolism
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Active Metabolite
Active Metabolite
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Regioisomers
Regioisomers
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Why is Losartan Synthesis Difficult?
Why is Losartan Synthesis Difficult?
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Importance of Purification
Importance of Purification
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ARBs
ARBs
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Benefits of ARBs over ACE inhibitors
Benefits of ARBs over ACE inhibitors
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What is Entresto?
What is Entresto?
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What does Sacubitril do?
What does Sacubitril do?
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What is Neprilysin?
What is Neprilysin?
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How does Entresto work?
How does Entresto work?
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What are some peptides targeted by Neprilysin?
What are some peptides targeted by Neprilysin?
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Why is Entresto important for CHF treatment?
Why is Entresto important for CHF treatment?
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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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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.