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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal

ChemistryChemistry 3/e 3/e

Chapter 22Chapter 22

ANTIULCER AGENTSANTIULCER AGENTS

Part 3: Proton pump inhibitorsPart 3: Proton pump inhibitors

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ContentsContents

Part 3: Proton pump inhibitors

23. Parietal Cells and the Proton Pump24. Proton Pump Inhibitors25. Mechanism of inhibition26. Design of omeprazole (Losec)

26.1. The lead compound26.2. Modification of the thiourea group26.3. Modify the imidazole ring26.4. Drug metabolism studies26.5. Add substituents to the heterocyclic rings26.6. Substituents varied on the pyridine ring26.7. Substituents varied on the benzimidazole ring

27. Esomeprazole (Nexium)28. Synthesis of Omeprazole

[11 slides]

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Lumen of the stomach

Proton pump

Receptors

Ion channels

Cck2H2

M3

ATP ADP + Pi

Canaliculus

The proton pumpThe proton pump • Pumps protons out of the parietal cell and potassium ions back inPumps protons out of the parietal cell and potassium ions back in• Requires energy - provided by hydrolysis of ATP to ADP, catalysed by Requires energy - provided by hydrolysis of ATP to ADP, catalysed by

ATPaseATPase• The proton pump is also called HThe proton pump is also called H++/K/K++-ATPase-ATPase• Chloride ions depart through a separate ion channelChloride ions depart through a separate ion channel• HCl is formed in the canaliculusHCl is formed in the canaliculus• The potassium ions exit the parietal cell as counterions for the chloride ions The potassium ions exit the parietal cell as counterions for the chloride ions

and are then pumped back inand are then pumped back in• A separate potassium ion channel is used for KA separate potassium ion channel is used for K++ ions leaving the cell ions leaving the cell

23. Parietal Cells and the Proton Pump23. Parietal Cells and the Proton Pump

H+ +K

HCl

Cl-

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24. Proton Pump Inhibitors24. Proton Pump Inhibitors

Pantoprazole

HN

N

OCHF2

S

O

N

OMeMeO

pyridine

methylsulfinyl'linker' benzamidazole

Omeprazole

HN

N

OMe

S

O

N

MeMeO

Me

Lansoprazole

HN

N

S

O

N

MeO

F3CRabeprazole

NaN

N

S

O

N

MeO

MeO

• Act as prodrugsAct as prodrugs• Activated by strongly acidic conditions found in the canaliculae Activated by strongly acidic conditions found in the canaliculae

of parietal cellsof parietal cells

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25. Mechanism of inhibition25. Mechanism of inhibition

HN

N OMe

SO

N

Me

OMe

Me

H

H+

N

N OMe

SO

N

Me

OMe

Me

H

H NH

N

OMe

H

N

S

O

Me Me

OMe

Spiro intermediate

H

-H+

N

N

OMe

N

S OH

MeMeO

Me

H

Sulfenic acid intermediate

-H2O

N

MeMeO

Me

S

N

N

OMe

Pyridinium sulfenamide structure

HS Protonpump

H

N

MeMeO

Me

NH

N

OMe

S SProtonpump

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• Originally an antiviral drugOriginally an antiviral drug• Inhibits gastric acid secretionInhibits gastric acid secretion• Liver toxicity due to the thioamide groupLiver toxicity due to the thioamide group

26. Design of omeprazole (Losec)26. Design of omeprazole (Losec)

26.1. The lead compound26.1. The lead compound

N

NH2

S

CMN 131

26.2. Modification of the thiourea group26.2. Modification of the thiourea group

N S

NH

N

H 77/67

• Inhibits gastric acid secretionInhibits gastric acid secretion• The pyridine ring and bridging CHThe pyridine ring and bridging CH22S moiety are important to activityS moiety are important to activity

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• Increase in activity due to the benzimidazole ringIncrease in activity due to the benzimidazole ring

26.3 Modify the imidazole ring26.3 Modify the imidazole ring

26.4 Drug metabolism studies26.4 Drug metabolism studies

• Timoprazole formed by metabolism of H124/26Timoprazole formed by metabolism of H124/26• Timoprazole is the active drugTimoprazole is the active drug• Pyridinylmethylsulfinyl benzimidazole structurePyridinylmethylsulfinyl benzimidazole structure• Side effect - inhibits iodine uptake by the thyroid glandSide effect - inhibits iodine uptake by the thyroid gland

N S

NH

N

H 124/26

benzimidazole

pyridine

N S

NH

NO

Timoprazole

26. Design of omeprazole (Losec)26. Design of omeprazole (Losec)

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• Potent antisecretory properties over long periods of timePotent antisecretory properties over long periods of time• No toxic side effects on the thyroidNo toxic side effects on the thyroid• No other serous side effectsNo other serous side effects

26.5 Add substituents to the heterocyclic rings26.5 Add substituents to the heterocyclic rings

N S

NH

NO

Picoprazole

CO2Me

Me

Me

26. Design of omeprazole (Losec)26. Design of omeprazole (Losec)

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26.6 Substituents varied on the pyridine ring26.6 Substituents varied on the pyridine ring

• Substituents which increase the basicity of the pyridine ring are good for Substituents which increase the basicity of the pyridine ring are good for activityactivity

• Promotes the mechanism of activationPromotes the mechanism of activation• Methyl substituents at the Methyl substituents at the metameta position have an inductive effect position have an inductive effect• Methoxy substituent are more effective at Methoxy substituent are more effective at parapara position than position than metameta

positionposition• Resonance effect increases electron density on the nitrogenResonance effect increases electron density on the nitrogen

N S

NH

NO CO2Me

Me

MeMeO

Me

H 159/69

• H159/69 is potent but chemically too labileH159/69 is potent but chemically too labile

N

MeMeO

Me R

N

MeMeO

Me R

N

MeMeO

Me RN

MeMeO

Me R

26. Design of omeprazole (Losec)26. Design of omeprazole (Losec)

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26.7 Substituents varied on the benzimidazole ring26.7 Substituents varied on the benzimidazole ring

• Substituents were varied to get the right balance of potency, chemical Substituents were varied to get the right balance of potency, chemical stability and synthetic accessibilitystability and synthetic accessibility

• Omeprazole was found to have the best balanceOmeprazole was found to have the best balance

• Launched in 1988 by AstraLaunched in 1988 by Astra• World’s biggest selling drugWorld’s biggest selling drug

Omeprazole

HN

N

OMe

S

O

N

MeMeO

Me

26. Design of omeprazole (Losec)26. Design of omeprazole (Losec)

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27. Esomeprazole (Nexium)27. Esomeprazole (Nexium)• Omeprazole has an asymmetric centreOmeprazole has an asymmetric centre

• The The SS-enantiomer has better potency and pharmacokinetic profile -enantiomer has better potency and pharmacokinetic profile

• Example of chiral switchingExample of chiral switching

HN

N

OMe

SN

MeMeO

Me

O

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28. Synthesis of Omeprazole28. Synthesis of Omeprazole

NCl

Pyridine portion

Me

OMe

Me

alkylchloride

+

N

NH

HS

OMe

Benzimidazole portion

thiol

NaOH

N

NH

S

OMe

N

Me

Me

MeO

N

NH

S

OMe

N

Me

Me

MeO

Omeprazole

O

O2H

OCl

meta-chloroperbenzoic acid