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24 Cards in this Set
- Front
- Back
Four major classes of drugs for anti-hypertensive therapy?
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1) B-blockers, 2). ACE-I, 3) ARBs, & 4) CCBs
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Four common structural features of Losartan and analogs?
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1) CO2H, CH2OH, akyl, or aryl group, 2) imidazole ring, 3) hydrocarbon side chain, & 4) ionized carboxylate or tetrazole entity
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What AA does the imidazole ring on losartan mimic?
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His in Ang II
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What AA does the hydrophobic side chain on losartan mimic?
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Ile in Ang II
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What AA does the acidic group mimic on losartan?
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Asp in Ang II
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What AA does the CO2H, CH2OH, akyl, or aryl group on losartan mimic?
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Phe on c-terminal of Ang II
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Why does the tetrazole in Losartan have better bioavailability than COOH?
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Charge delocalization and more metabolically stable- often excreted unchanged
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Is -OH more or less lipophilic than -COOH?
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more lipophilic (e.g. losartan development)
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Is the metabolite of losartan more or less active than losartan itself?
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MORE active- but still not a prodrug, because losartan does have some activity
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How is losartan metabolized?
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14% to active carboxylic acid (more potent), 80% excreted unchanged, the rest is metabolized to inactive metabolites
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What CYP enzymes are used to metabolize Losartan?
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2C9 and 3A4
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Ester prodrugs of ARBs (2)
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Candesartan cilexetil and olmesartan medoxomil
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Losartan (class)
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ARB
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Key interactions of Losartan with AT1 receptor (2)
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Arg and Lys with Tetrazole ring
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How does Ca cause muscle contraction?
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Binding of Ca2+ to troponin caused a conformational change in tropomyosin that uncovers myosin binding sites on the actin filiment, thus facilitating the cross-bridge cycling process.
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Nifedipine (class and subclass)
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CCB - 1,4-dihydropyridine
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SAR of dihydropyridines
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1) 1, 4- dihydropyridine ring, 2) R2 and R3 are esters, 3) X-substituted phenyl ring, 4) substituted X blocks rotation (perpendicular conformation is locked) (ORTHO OR META)
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Conformational restriction of Dihydropyridines
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Ortho or meta substitution in phenyl ring locks perpendicular conformation (no rotation allowed)
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What is the Hantzsch reaction?
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Synthesis of Dihydropyridines
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What are dihydropyridines?
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CCBs
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Building blocks for the Hanzsch reaction
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NH3, aldehyde, 2 (ketone ester combos) --> three molecules of water are lost in the condensation reaction
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What is the conformation of the o-NO2 group of nifedipine for activity?
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Perpendicular
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Metabolism of 1,4-dihydropyridines
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1) CYP3A4 oxidation to more stable pyridine, 2) esterase hydrolysis, 3) glucuronic acid conjugates
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How to synthesize unsymmetric dihydropyridines?
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Stepwise Hantzsch reaction (add NH3 and aldehyde to each of the ketone/ester combos first, then combine the two)
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