Download (4Mb) - Etheses - Saurashtra University

Part-1Review on Antiulcer Literature1.5. Irreversible Proton Pump Inhibitors1.5.1. IntroductionIn early 1970’s, anti-secretory activity of the analogs of the pyridylthioacetamide (CMN)29 was studied. This led to the discovery of a class of extremely efficacious inhibitors ofgastric acid secretion, with a novel mode of action, of which the pyridylmethylbenzimidazole sulfoxide, timoprazole 16, is the archetypal structure. Meanwhile H + /K + -ATPase enzyme was also discovered by other research group that enabled thedemonstration that compounds related to timoprazole were non-competitive inhibitors ofthe enzyme. This led to the synthesis of picoprazole 17 and omeprazole 18, new drugs forthe treatment of peptic-ulcer and related diseases. This work also helped in generating andunderstanding the way in which the enzyme operates. 50SHNSON NH 2NCMN 29Timoprazole 16NHNOONSO Picoprazole 17NFigure 15: Structure of some initial PPIs1.5.2. Mechanism of ActionOn studying the mechanism of action of these inhibitors of the H + /K + -ATPase, severalsalient features of their action became apparent like; a) the weak basicity of thecompounds (pKa≈4), allowing them to accumulate in the acid space adjacent to their siteof action (i.e., secretory canaliculus of the parietal cells); b) the sulfoxides themselveshave no intrinsic activity, but under the influence of acid undergo a chemicalrearrangement to an active species; iii) the active species is thiophillic in nature andcovalently binds to thiol functions like cysteinyl residues generating disulfide bridges tothe enzymes, thereby causing its inactivation. 5019