MedChem for dyspepsia, GERD and PUD

Chemistry of antacids

CaCo₃ + 2HCl ---->   CaCl₂ + H₂O + CO₂

• physical interaction to neutralize stomach pH

H2-Receptor Antagonists (H2RA)

• reduce acid secretion by blocking the actions of histamine and gastrin

Burimamide

• not orally active in acidic pH of the stomach

• pharmacophore: thiourea

  • side effects like decreasing WBC

Metiamide

• stable in the acidic pH of the stomach

• pharmacophore: thiourea

  • side effects like decreasing WBC

Cimetidine

• stable in the acidic pH of the stomach

• pharmacophore:

  • guanidino - does not have the side effects of decreasing WBC, contains an EWG that enhances binding affinity

  • imidazole - causes it to inhibit CYP450 enzymes

• contains double bonds - sensitive to light

Ranitidine

• stable in the acidic pH of the stomach

• pharmacophore:

  • guanidino - does not have the side effects of decreasing WBC, contains an EWG that enhances binding affinity

  • furan- weaker interactions with CYP450 so fewer drug-drug interactions

• contains double bonds - sensitive to light

• 5x more potent and selective vs cimetidine

• tertiary amine off of furan ring will carry a positive charge and allow for H-bonding with Asp

Famotidine

• pharmacophore: thiazole

  • does not interact with CYP450 enzymes

• risk of sulfa-allergies

• contains EWG - very potent binding affinity

• contains double bonds- sensitive to light

• 20x more potent and selective vs cimetidine

• longer duration or action

Nizatidine

• pharmacophore: thiazole

  • does not interact with CYP450 enzymes

• contains EWG - very potent binding affinity

• contains double bonds- sensitive to light

• excellent bioavailability

SAR of H2RAs

• heterocyclic ring essential

  • 5 member > 6 member

• sulfur atom in side chain provides oral bioavailability (vs. carbon or oxygen)

• terminal EWG provides optimum binding affinity

• 5 atom separation is best for binding affinity

Steps for PPI in vivo bioconversion

all prodrugs!

• at acidic pH of stomach protonation of pyridine nitrogen

• can then also get a protonated benzimidazole ring additionally

• will then get protonation of imidazole nitrogen II

• convert to active metabolite - cyclic “sulfenamide”

  • binds covalently to H+/K+ ATPase

• also inhibit CYP2C19 and CYP2C9

Omeprazole

• pharmacophore: benzimidazole

• racemic mixture

• C5 = EDG - increase nucleophilicity and allow for protonation

• Pyridine: substituents are EDG - increase nucleophilicity and allow for protonation

Esomeprazole

• pharmacophore: benzimidazole

• (S)- enantiomer of omeprazole

  • better oral bioavailability vs racemic mixture

• C5 = EDG - increase nucleophilicity and allow for protonation

• Pyridine: substituents are EDG - increase nucleophilicity and allow for protonation

Lansoprazole

• pharmacophore: benzimidazole

• racemic mixture

• superior oral bioavailability among PPIs

• Pyridine: substituents EWG (trifluoroethoxy)- decrease nucleophilicity and less likely to protonate

• most potent inhibitor

Pantoprazole

• pharmacophore: benzimidazole

• racemic mixture

• C5 = EWG - decrease nucleophilicity and slow to protonate

• Pyridine: substituents are EDG

  • C5 is dominant in considering the time to proteinate

• slower conversion to active compared to the other PPIs

Rabeprazole

• pharmacophore: benzimidazole

• racemic mixture

• Pyridine: substituents are EDG (methoxypropoxy) - increase nucleophilicity and allow for protonation

• fast conversion to active compared to the other PPIs

SAR of PPIs

• benzimidazole provides optimum activity

  • R4 with EDG favour good activity

• sulfoxide between the ring structures is essential for activity

• pyridine provides optimum activity

  • R2/R3 with EDG are favoured

  • R1 with EDG is favoured (OCH3 is optimum activity)

• C6 and N1 substitution leads to loss of activity

PPIs and clopidogrel interaction

• clopidogrel is a prodrug and requires metabolism by CYP2C19

• PPIs can interfere with bioactivation and therapeutic effect b/c it can inhibit to CYP2C19

Misoprostol

• prodrug

  • ester converts to carboxylic acid

• prostanoid derivative (PGE1 derivative)

• undergoes phase II conjugation - short half-life

Sucralfate

• sucrose derivative

  • contains sulfates linked to aluminum hydroxide (neutralize HCl)

  • contains glycosidic bond - not stable at acidic pH

• forms a protective layer

Metoclopramide

• pharmacophore: benzamide

  • can perform H-bonding

  • methoxy group important for binding affinity

• tertiary amine is very lipophilic so can get into CNS

• 5-HT4 agonist and D2-antagonist

Domperidone

• pharmacophore: benzimidazole

  • very polar - so won’t cross BBB

• D2 and D3 antagonist

• reduced CNS effects relative to metoclopramide

• N in 6 member ring will also become charged