(H-ATPASE INHIBITING 2-[(2-PYRIDYLMETHYL)SULFINYL]BENZIMIDAZOLES .4. A NOVEL SERIES OF DIMETHOXYPYRIDYL-SUBSTITUTED INHIBITORS WITH ENHANCED SELECTIVITY - THE SELECTION OF PANTOPRAZOLE AS A CLINICAL CANDIDATE(,K+))

[(Pyridylmethyl)sulfinyl]benzimidazoles 1 (PSBs) are a class of highly potent antisecretory (H+,K+)-ATPase inhibitors which need to be activ ated by acid to form their active principle, the cyclic sulfenamide 4. Selective inhibitors of the (H+,K+)-ATPase in vivo give rise to the n onselective thiophile 4 solely at low pH, thus avoiding interaction wi th other thiol groups in the body. The propensity to undergo the acid- catalyzed transformation is dependent on the nucleophilic/electrophili c properties of the functional groups involved in the formation of 2 s ince this step is both rate-determining and pH-dependent. The aim of t his study was to identify compounds with high (H+,K+)-ATPase inhibitor y activity in stimulated gastric glands possessing acidic pH, but low reactivity (high chemical stability) at neutral pH as reflected by in vitro (Na+,K+)-ATPase inhibitory activity. The critical influence of s ubstituents flanking the pyridine 4-methoxy substituent present in all derivatives was carefully studied. The introduction of a 3-methoxy gr oup gave inhibitors possessing a combination of high potency, similar to omeprazole and lansoprazole, but increased stability. As a result o f these studies, compound 1a (INN pantoprazole) was selected as a cand idate drug and is currently undergoing phase III clinical studies.