Inhibitors of Gastric Acid Secretion

Roberts, Sonia P.; McDonald, Iain M.

doi:10.1002/0471266949.bmc061

Cited by 2 publications

(1 citation statement)

References 194 publications

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“…The secretion of gastric acid in parietal cells is due to the presence of food in the stomach or the intestine and is also due to the taste, smell, sight, or thought of food. ,, Gastric acid is secreted followed by the activation of histamine, acetylcholine or gastrin receptors (the H2, M3, and CCK2 receptors, respectively) located in the basolateral membrane of the parietal cells. The H2, M3, and CCK2 receptors initiate signal transduction pathways that triggers the activation of the H + ,K + -ATPase which causes acid secretion .…”

Section: Introductionmentioning

confidence: 99%

Revealing the Mechanistic Pathway of Acid Activation of Proton Pump Inhibitors To Inhibit the Gastric Proton Pump: A DFT Study

2016

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Acid-related gastric diseases are associated with disorder of digestive tract acidification due to the acid secretion by gastric proton pump, H,K-ATPase. Omeprazole is one of the persuasive irreversible inhibitor of the proton pump H,K-ATPase. However, the reports on the mechanistic pathway of irreversible proton pump inhibitors (PPIs) on the acid activation and formation of disulfide complex are scarce in the literature. We have examined the acid activation PPIs, i.e., timoprazole, S-omeprazole and R-omeprazole using M062X/6-31++G(d,p) in aqueous phase with SMD solvation model. The proton pump inhibitor is a prodrug and activated in the acidic canaliculi of the gastric pump H,K-ATPase to sulfenic acid which can either form another acid activate intermediate sulfenamide or a disulfide complex with cysteine amino acid of H,K-ATPase. The quantum chemical calculations suggest that the transition state (TS5) for the disulfide complex formation is the rate-determining step of the multistep acid inhibition process by PPIs. The free energy barrier of TS5 is 5.5 kcal/mol higher for timoprazole compared to the S-omeprazole. The stability of the transition state for the formation of disulfide bond between S-omeprazole and cysteine amino acid of H,K-ATPase is governed by inter- and intramolecular hydrogen bonding. The disulfide complex for S-omeprazole is thermodynamically more stable by 4.5 kcal/mol in aqueous phase compared to disulfide complex of timoprazole, which corroborates the less efficacy of timoprazole as irreversible PPI for acid inhibition process. It has been speculated that sulfenic acid can either form sulfenamide or a stable disulfide complex with cysteine amino acid residue of H,K-ATPase. The M062X/6-31++G(d,p) level of theory calculated results reveal that the formation of tetra cyclic sulfenamide is unfavored by ∼17 kcal/mol for S-omeprazole and 11.5 kcal/mol for timoprazole compared to the disulfide complex formation in each case. The DFT calculations have further shed light on the acid activation process of R- and S-isomers of omeprazole. The calculated results suggest that the efficacy of these isomers lie on their metabolic pathway and excretion from human body.

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Section: Introductionmentioning

confidence: 99%

Revealing the Mechanistic Pathway of Acid Activation of Proton Pump Inhibitors To Inhibit the Gastric Proton Pump: A DFT Study

2016

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Antihistamines, Proton Pump Inhibitors and Related Drugs

Faruk Khan

2024

Medicinal Chemistry for Pharmacy Students

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This chapter is a comprehensive account of the medicinal chemistry of antihistamines, H2 receptor (H2R) blockers, H3 receptor (H3R) blockers, and proton pump inhibitors (PPIs). It provides the mechanism of drug action and detailed structure-activity relationship (SAR) of the drugs in these classes to give the knowledge base for pharmacists. After studying this chapter, students will be able to: Describe the physiochemical properties of histamine and histamine receptors. • Identify chemical classifications and describe the SAR of antihistamines, H2R and H3R antagonists. • Differentiate receptor binding patterns and structural features between histamine receptor agonists and antagonists. • Distinguish between sedating and non-sedating antihistamines, as well as the first-, second- and third-generation antihistamines. • Describe the structural features of cromolyn and related mast cell stabilizers and their therapeutic applications. • Discuss the proton pump inhibitors, including their development, mechanism of action, and structural and physicochemical features. • Apply the medicinal chemistry principles to the clinically relevant case studies. • Explain the drug discovery story of representative drugs of different classes.

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Inhibitors of Gastric Acid Secretion

Cited by 2 publications

References 194 publications

Revealing the Mechanistic Pathway of Acid Activation of Proton Pump Inhibitors To Inhibit the Gastric Proton Pump: A DFT Study

Revealing the Mechanistic Pathway of Acid Activation of Proton Pump Inhibitors To Inhibit the Gastric Proton Pump: A DFT Study

Antihistamines, Proton Pump Inhibitors and Related Drugs

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