PHAR303 Final Exam - Sample Questions PDF

PHAR303 Final Exam – Sample Questions 1. What strategies are recommended to counteract the effects of Angiotensin II, known for its predominant role in elevating blood pressure through the renin-angiotensin pathway? Strategies to mitigate the effects of Angiot...

PHAR303 Final Exam – Sample Questions 1. What strategies are recommended to counteract the effects of Angiotensin II, known for its predominant role in elevating blood pressure through the renin-angiotensin pathway? Strategies to mitigate the effects of Angiotensin II involve inhibiting the angiotensin-converting enzyme (ACE), blocking the angiotensin receptors, or impeding the activity of the renin enzyme. These approaches aim to disrupt different points along the renin-angiotensin pathway to reduce the influence of Angiotensin II on blood pressure regulation and related physiological effects. 2. How do high levels of angiotensin II contribute to hypertension through both rapid and slow pressor responses? High levels of angiotensin II contribute to hypertension through two main mechanisms. Rapidly, angiotensin II causes vasoconstriction, which increases blood pressure. Slowly, it stimulates the adrenal gland to release aldosterone, an enzyme that promotes water and electrolyte retention. This retention increases blood volume, leading to sustained hypertension. 3. The ACE compounds can be subclassified into three groups based on their chemical composition: sulfhydryl-containing inhibitors (exemplified by captopril), Dicarboxylate-containing inhibitors (exemplified by enalapril), and Phosphonate-containing inhibitors (exemplified by fosinopril). 4. The sulfhydryl group of captopril contributes to both its excellent inhibitory activity and two common side effects. What are these side effects? The sulfhydryl group of captopril is associated with two common side effects: skin rashes and taste disturbances such as metallic taste or loss of taste. Additionally, the presence of the sulfhydryl group contributes to a shorter half-life due to the compound's increased susceptibility to metabolism, especially the formation of disulfide dimers. 5. How can the higher potency of enalaprilat (approximately 10-fold more potent) compared to captopril be explained? 1  Angiotensin 1 – Enalaprilat Angiotensin converting Captopril enzyme (ACE) complex The increased potency of enalaprilat compared to captopril is attributed to its enhanced binding capability, which is proposed to stem from its ability to mimic the transition state of angiotensin I hydrolysis more effectively. This improved mimicry of the transition state results in stronger and more specific interactions with the target enzyme, consequently leading to greater inhibitory potency. 6. How can the replacement of histidine in angiotensin I by a methyl group explain the favorable affinity of enalaprilat over the natural substrate? Angiotensin 1 – Angiotensin Enalaprilat binding converting profile enzyme (ACE) complex The replacement of histidine, which includes an imidazole ring, with a methyl group in Enalaprilat enhances its affinity over the natural substrate, angiotensin I, due to a reduction in desolvation effects. The imidazole ring of histidine, being hydrophilic, negatively affects drug affinity by contributing to significant desolvation effects without providing valuable physical interactions. Substituting this hydrophilic group with a lipophilic methyl group reduces the desolvation effect, thereby improving the ligand-protein recognition and favoring the affinity of enalaprilat over the natural substrate. 7. How does the replacement of leucine in angiotensin I by a pyrrolidine group elucidate the favorable affinity of enalaprilat compared to the natural substrate? 2  Angiotensin 1 – Angiotensin Enalaprilat binding converting profile enzyme (ACE) complex Substituting the isobutyl chain (-CH2-CH(CH3)2) of leucine in angiotensin I with a pyrrolidine ring in enalaprilat reduces ligand flexibility, thereby increasing rigidity. This enhanced rigidity of the ligand contributes to improved ligand recognition, ultimately leading to greater overall affinity of enalaprilat compared to the natural substrate. 8. Which structural features of Enalaprilat contribute to its high hydrophilicity and low lipophilicity? The high hydrophilicity and low lipophilicity of Enalaprilat are primarily attributed to its structural components, particularly the presence of two carboxylate groups and a secondary amine. These features collectively render Enalaprilat less lipophilic and contribute to its reduced oral bioavailability. 9. Considering the functional groups and pKa values present in enalaprilat's structure, what charges would it hold in the stomach (pH = 1.5) and small intestine (pH = 7), and based on this? Basic (Pka = 8) Acidic (Pka = 3.5) Acidic (Pka = 3.5) 3 In the stomach (pH = 1.5), the acidic functional groups of enalaprilat, being stronger acids than the stomach's pH, will remain non-ionized, while the secondary amine will be positively charged. In contrast, in the small intestine (pH = 7), both the carboxylic acid groups and the secondary amine will be ionized, resulting in two negative charges and one positive charge on the molecule (forms a zwitterion ion). 10. When one of the carboxylic acids in Enalaprilat is esterified to enhance its bioavailability, how does this modification increase lipophilicity? Basic Basic Pka=8 Pka=5.49 Enalapril Enalaprilat Esterification enhances the lipophilicity in two ways: Firstly, the conversion of a hydrophilic carboxylic acid group to an ester bond imparts more lipophilic characteristics to the molecule. Secondly, esterification decreases the pKa value of the secondary amine (reducing its basicity), resulting in a non-ionized form inside the intestine (pH = 7). In contrast, Enalaprilat remains ionized in the intestine due to its original structure. Additionally: The scientific concept behind esterifying only one carboxylic acid group instead of both is to allow the molecule to achieve the zwitterion form, where one group carries a positive charge and the other carries a negative charge. At a neutral pH of 7, the overall charge of the molecule becomes zero. This optimal condition of having a neutral charge enhances gastrointestinal absorption and bioavailability of the compound, as it can more readily traverse biological membranes. 11. Despite enalapril demonstrating a 1,000-fold decrease in in vitro activity compared to enalaprilat, both IV-administered enalapril (prodrug/inactive form) and enalaprilat (active form) produce similar effects on angiotensin II production. How can this phenomenon be explained? 4  Esterases Enalapril Enalaprilat This discrepancy can be attributed to the absence of esterase enzymes in in vitro conditions. Enalapril, as a prodrug, requires enzymatic conversion by esterases to its bioactive form, enalaprilat. However, upon IV administration in vivo, esterase enzymes are present and swiftly convert the prodrug (inactive form) directly into the active form, enalaprilat. This rapid conversion in vivo leads to similar effects on angiotensin II production despite enalapril showing significantly lower in vitro activity. 12. Which functional groups possess the capability to achieve optimal binding with the Zn+2 within the binding site of the angiotensin-converting enzyme (ACE)? The phosphinic acid, sulfhydryl, and carboxylate groups are known to form similar binding interactions with the Zn+2 ion within the binding site of the angiotensin-converting enzyme (ACE), facilitating optimal binding. 13. In terms of the structural-activity relationship (SAR) of angiotensin-converting enzyme inhibitors (ACEI), which one among the provided drugs is not considered active? Compound (d), lacking a carboxylic acid at the N-ring, is the inactive agent among the options provided. The presence of a carboxylic acid in the N-ring is crucial in mimicking the C-terminal carboxylate of ACE substrates (Angiotensin). The absence of this carboxylic acid group in compound (d) results in its loss of activity as an ACE inhibitor. 14. Based on Q13, which of the depicted structures are the most potent? 5 Structure (b) is the most potent one as it includes a hydrophobic substituent at the pyrrolidine ring, so enhancing the interaction profile via adding additional hydrophobic interactions and filling more space within the binding site. 15. Lisinopril, an angiotensin-converting enzyme inhibitor (ACEI), is notably highly hydrophilic yet orally active. How could you explain this based on the charge state indicated in its structure within the duodenum? One possible explanation is that within the duodenum, lisinopril might exist as a di-zwitterion, containing two negative and two positive charges, allowing the ionized groups to internally bind to each other. This structural configuration potentially enables lisinopril to pass through the lipid bilayer with an overall net neutral charge despite its highly hydrophilic nature, potentially facilitating its oral activity. 16. In the structural-activity relationship (SAR) of angiotensin receptor blockers (ARBs), which R group should be replaced by a tetrazole functional group at the ortho position to significantly enhance activity? To significantly enhance activity within the SAR of ARBs, the R1 group located at the ortho position should be replaced by a tetrazole functional group. This substitution gives rise to the drug Losartan, where R1 is substituted with a tetrazole ring, contributing to increased activity. 17. Why is the tetrazole ring considered an optimal bioisostere for the carboxylic acid functional group to enhance bioavailability? The tetrazole ring is considered an optimal bioisostere for the carboxylic acid functional group due to several factors. Firstly, it shares similar electronic and steric configurations with the 6  carboxylic acid group. Additionally, the tetrazole functional group provides more lipophilic characteristics compared to the carboxylic acid group, thereby enhancing lipophilicity. This increased lipophilicity can have a beneficial effect on enhancing bioavailability. 18. What is the active metabolite of Losratan? Approximately 14% of a dose of losartan is oxidized by the isozymes CYP2C9 and CYP3A4 to produce EXP-3174, a noncompetitive receptor antagonist that is 10- to 40-fold more potent than losartan. Here the hydroxy methyl group is oxidized to carboxylic acid. 19. Among the provided compounds, which one is an active agent based on the structure- activity relationship (SAR) of calcium channel blockers? Compound (b) is the only active agent according to SAR studies. The presence of the 1,4- dihydropyridine (DHP) ring, as in compound (b), is crucial for activity in calcium channel blockers. Substitutions at the N1 position, as seen in compound (a), or a reduced (pyridine) ring system, as in compound (c), significantly reduce or abolish the activity of these compounds. 20. Define the hyperlipidemia? An excess plasma concentration of one or more of these compounds: cholesterol, cholesterol esters, triglycerides, and phospholipids 21. How the Lipoproteins are classified? 7 lipoproteins are classified according to their density and identified as very-low-density lipoproteins (VLDLs) which contains a very low percentage of protein, intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs) which contains a high percentage of protein. 22. What is the primary control enzyme involves in the cholesterol biosynthesis, and which is it action? the primary control enzyme is the HMG–CoA reductase that convert 3-hydroxy-3-methylglutaryl (HMG)–CoA to mevalonic acid 23. Mention one example of a bile acid sequestrant and describe the main characteristics of these agents. Answer: An example of a bile acid sequestrant is cholestyramine. Bile acid sequestrants are highly positively charged molecules that bind to the negatively charged bile acids in the intestine. This binding inhibits the lipid solubilizing activity of bile acids, thereby blocking the absorption of cholesterol. 24. Mentioned three drug examples that serve as HMG-COA reductase inhibitors? Mevastatin, Simvastatin, Atorvastatin. 25. The activity of HMGRIs is sensitive to what? the stereochemistry of the lactone ring , the ability of the lactone ring to be hydrolyzed and the length of bridge connecting the two ring systems 26. Why Pravastatin is more hydrophilic that simvastatin or lovastatin? And what are the Proposed advantages of this enhanced hydrophilicity? 8 Pravastatin, a ring-opened dihydroxy acid with a 6-hydroxyl group, is much more hydrophilic than either lovastatin or simvastatin. The Proposed advantages of this enhanced hydrophilicity are: minimal penetration into the lipophilic membranes of peripheral cells, better selectivity for hepatic tissues, and a reduction in the incidence of side effects seen with lovastatin and simvastatin. 27. The following drug modification from compound D to Ezetimib, including the introduction of hydroxyl and p-Fluorine groups, results in what? Ezetimib e The introduction of hydroxyl lead to localize the compound in the intestine (by improving water solubility) and the introduction of p-fluoro groups to block undesirable metabolism. 28. What is the active form of p-chlorophenoxyisobutyrate (Clofibrate) which is a prodrug? 29. Based on the previous question. What are the advantages observed when introducing a chloro functional group at the para-position? Substitution at the para position of the aromatic ring with a chloro group or a chlorine-containing cyclopropyl ring produces compounds with significantly longer half-lives due to improving the structural lipophilicity. 30. The pka of pyridine ring within nicotinic acid structure is very low (Pka=2), what is reason behind that? 9 The reason behind that is the strong electron withdrawing effect of carboxylic acid which will decrease the electron density of the ring, so decreasing the electron density of N, then finally decreases the its basicity. Good luck 10