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 What is the pharmacophore is for all currently marketed PPIs?
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2-pyridylmethylsulfinylbenzimidazole
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Differences between various PPIs are found in what areas of the pharmacophore?
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Substituents placed on the pyridine and benzimidazole rings
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(True/False) The Sulfinyl moiety on PPI parent drugs is sufficiently reactive to form essential disulfide bond with proton pump CYS residues.
False, is not sufficienly reactive enough (prodrugs)
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Are PPIs active or prodrugs in the parent form?
Prodrugs
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Do PPIs require enzymatic activation?
No
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What form will PPIs be in in the blood stream, ionized or unionized?
Completely unionized
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What form will PPIs be in in the stomach, ionized or unionized?
Highly ionized
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What are the functions of the electron donating groups on the PPI pharamcophore?
↑ % of pyridine N existing in ionized form, ↑ nucleophilic character of pyridine N in unionized form, ↑rate of formation of active sulfenic acid/sulfonamide rearrangement products
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How does the pKa of the benzidamazole N3 relate to the Pyridine N?
Benzidamazole N3 has a lower pKa than the Pyridine N
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How does the pKa of the benzidamazole N3 relate to the pKa of the parietal cells?
Benzidamazole N3 has a lower pKa than the Parietal Cells
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Which ring is protonated first:
First the pyridine ring, then the Benzimidazole ring
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Why is it important that the benzimidazole N3 is cationic?
Critical to PPI activation, ↑electrophilicity of C2 by pulling the e- through the sigma bonds, which ↑intramolecular attack
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Why is it important that e- donating substituents are present on C5 of the benzimidazole ring?
They push electrons to the N3, increasing the % existing in the cationic form
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