Abstract：
:[(Pyridylmethyl)sulfinyl]benzimidazoles 1 (PSBs) are a class of highly potent antisecretory (H+,K+)-ATPase inhibitors which need to be activated by acid to form their active principle, the cyclic sulfenamide 4. Selective inhibitors of the (H+,K+)-ATPase in vivo give rise to the nonselective thiophile 4 solely at low pH, thus avoiding interaction with other thiol groups in the body. The propensity to undergo the acid-catalyzed transformation is dependent on the nucleophilic/electrophilic properties of the functional groups involved in the formation of 2 since this step is both rate-determining and pH-dependent. The aim of this study was to identify compounds with high (H+,K+)-ATPase inhibitory 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 substituents flanking the pyridine 4-methoxy substituent present in all derivatives was carefully studied. The introduction of a 3-methoxy group gave inhibitors possessing a combination of high potency, similar to omeprazole and lansoprazole, but increased stability. As a result of these studies, compound 1a (INN pantoprazole) was selected as a candidate drug and is currently undergoing phase III clinical studies.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Kohl B,Sturm E,Senn-Bilfinger J,Simon WA,Krüger U,Schaefer H,Rainer G,Figala V,Klemm Kdoi
10.1021/jm00084a010keywords:
subject
Has Abstractpub_date
1992-03-20 00:00:00pages
1049-57issue
6eissn
0022-2623issn
1520-4804journal_volume
35pub_type
杂志文章abstract：:A series of 1-(4-fluorophenyl)-1H-indoles substituted at the 3-position with 1-piperazinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperidinyl was synthesized. Within all three subseries potent dopamine D-2 and serotonin 5-HT2 receptor affinity was found in ligand binding studies. Quipazine-induced head twitches in rat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00084a014
更新日期：1992-03-20 00:00:00
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abstract：:Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15...
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更新日期：2006-01-12 00:00:00
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更新日期：2008-07-24 00:00:00
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doi：10.1021/acs.jmedchem.5b01720
更新日期：2016-01-14 00:00:00
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doi：10.1021/jm970549h
更新日期：1997-12-19 00:00:00
abstract：:Inhibitor of secreted frizzled related protein-1 (sFRP-1) would be a novel potential osteogenic agent, since loss of sFRP-1 affects osteoblast proliferation, differentiation, and activity, resulting in improved bone mineral density, quality, and strength. We have identified small molecule diarylsulfone sulfonamide der...
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更新日期：2008-12-25 00:00:00
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更新日期：2009-12-10 00:00:00
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更新日期：2013-09-26 00:00:00
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pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01280
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journal_title：Journal of medicinal chemistry
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doi：10.1021/jm401396p
更新日期：2014-03-13 00:00:00
abstract：:A series of 2,3-diaminopropionanilides was synthesized by acylation of mono- and disubstituted aniline derivatives with 2,3-dibromopropionyl chloride and subsequent amination with the appropriate secondary amines. The target compounds were evaluated in mice for antiarrhythmic efficacy against chloroform-induced tachyc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00141a008
更新日期：1981-09-01 00:00:00
abstract：:New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2...
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pub_type： 杂志文章
doi：10.1021/jm00035a012
更新日期：1994-04-29 00:00:00
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更新日期：2002-06-20 00:00:00
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更新日期：2020-03-26 00:00:00
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更新日期：1989-08-01 00:00:00
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更新日期：1998-01-29 00:00:00
abstract：:Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound als...
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更新日期：2009-11-26 00:00:00
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更新日期：1992-11-13 00:00:00
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更新日期：1987-11-01 00:00:00
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pub_type： 杂志文章
doi：10.1021/jm00243a021
更新日期：1975-09-01 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00377a013
更新日期：1984-11-01 00:00:00
abstract：:Current drugs for the treatment of seizure disorders, although effective in many patients, still suffer from a number of failures and are not effective in some forms of resistant epilepsies. Historically, many of these drugs have multiple mechanisms of action including calcium and sodium channel blockade as well as GA...
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