- Importance of the azole moiety of cimetidine derivatives for the inhibition of human multidrug and toxin extrusion transporter 1 (hmate1)
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Herein, we describe the design and synthesis of cimetidine analogs, as well as their inhibitory activity toward the human multidrug and toxin extrusion transporter 1 (hMATE1), which is related to nephrotoxicity of drugs. Cimetidine is the histamine H2-receptor antagonist, but also inhibits hMATE1, which is known to cause renal impairment. We designed and synthesized cimetidine analogs to evaluate hMATE1 inhibitory activity to reveal whether the analogs could reduce the inhibition of hMATE1. The results showed that all analogs with an unsubstituted guanidino group exhibited hMATE1 inhibitory activity. On the other hand, there was a clear difference in the hMATE1 inhibitory activity for the other compounds. That is, compounds with a methylimidazole ring exhibited hMATE1 inhibition, while compounds with a phenyl ring did not. The results suggest that the ability to form hydrogen bonds at the azole moiety is strongly involved in the hMATE1 inhibition.
- Shinya, Susumu,Kawai, Kentaro,Tarui, Atsushi,Karuo, Yukiko,Sato, Kazuyuki,Matsuda, Masaya,Kitatani, Kazuyuki,Kobayashi, Naoki,Nabe, Takeshi,Otsuka, Masato,Omote, Masaaki
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p. 905 - 912
(2021/09/06)
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- Isohistamines and homologues as components of H2-antagonists. 22nd Comm.: H2-antihistaminics
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Starting with isohistamines and their homologues or from appropriately hydrogenated imidazo[1,2-c]pyrimidines, imidazo[1,2-c][1,3]diazepines and -diazocines, H2-antihistaminics with cyanoguanidine and 2-nitro-1,1-ethenediamine structure were prepared and tested for their H2-antagonistic activity on the isolated guinea-pig atrium and on the histamine-stimulated acid secretion of the anaesthetized rat. While four of the cyanoguanidines were weaker in comparison to cimetidine, or inactive, thirteen others possessed markedly stronger activity, whereby the activity reaches a maximal effect at the rat stomach when cyanoguanidine and imidazole ring are connected with a three-membered chain. The activity of the 2-nitro-1,1-ethenediamines exceeds that of the comparable cyanoguanidines in both test models.
- Buschauer,Postius,Szelenyi,Schunack
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p. 1025 - 1029
(2007/10/02)
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- Process for preparing 5-methyl-4-imidazolecarboxylic acid esters
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A process for the preparation of 5-methyl-4-imidazolecarboxylic acid esters from acetoacetic acid esters. The products of this process are useful as intermediates for preparing cimetidine.
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- Synthesis and h2-antihistaminic activity of n,n'-bisimidazole-substituted thioureas, cyanoguanidines and 2-nitro-1,1-ethenediamines 10. C: H2-antihistaminics
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In studies on structure-activity relationships of histamine H2-receptor antagonists, N,N'-bis(2-[(4-imidazolyl)-methylthio]-ethyl)-substituted thioureas, cyanoguinidines, and 2-nitro-1,1-ethenediamines with different C-5 methylation of the imidazole rings were prepared and tested for their H2-antihistaminic activity on the isolated guinea-pig atrium and the stimulated gastric acid secretion of the anaesthetized rat. When tested on isolated guinea-pig atrium, substances with both C-5 positions methylated (5b, 7b, 9b) proved to be up to seven times more active than metiamide, whereas inhibition of gastric acid secretion turned out to be less marked. While equally methylated thioureas and cyanoguanidines showed same potency, the 2-nitro-1,1-ethenediamines clearly possessed lower activity.
- Borchers,Engler,Szelenyi,Schunack
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p. 1509 - 1512
(2007/10/02)
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- Imidazolemethylphosphonium salts
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New imidazolemethylphosphonium salts having a degradable group at the 2-position which are useful intermediates for preparing histamine H2 antagonists.
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- Process for preparing 4-substituted imidazole compounds
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A process for preparing 4-(oxy, thio or amino)methylimidazole compounds via displacement of the trisubstituted phosphonium group from 4-(trisubstituted phosphonium)methylimidazole compounds is disclosed.
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- Process for preparing 4-(hydroxymethyl)imidazole compounds
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An improved process for the preparation of 4-(hydroxymethyl)imidazoles by reducing 4-imidazolecarboxylic acid esters using an alkali metal or calcium in liquid ammonia with an additional proton source provided during the reaction or upon workup.
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- CERTAIN THIAZOLES AND OXAZOLES
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The compounds are N,N'-substituted thioureas, ureas and guanidines which are H-2 histamine receptor inhibitors. Two compounds of this invention are N,N'-bis 2-((4-methyl-5-imidazolyl)methylthio) ethyl!thiourea and N,N'-bis 2-((4-methyl-5-imidazolyl)methylthio)ethyl!-N"-cyanoguanidine. "
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- PHARMACOLOGICALLY ACTIVE GUANIDINE COMPOUNDS
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The compounds are substituted thioalkyl-, aminoalkyl-and oxyalkyl-guanidines which are inhibitors of histamine activity.
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- Process of reduction
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An electrochemical process for preparing 4-(hydroxymethyl)-imidazoles, which are useful as chemical intermediates.
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- PHARMACOLOGICALLY ACTIVE GUANIDINE COMPOUNDS
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The compounds are substituted thioalkyl-, aminoalkyl-and oxyalkyl-guanidines which are inhibitors of histamine activity.
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