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24 Cards in this Set

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