- Regioselective hydroxylation pathway of tenatoprazole to produce human metabolites by Bacillus megaterium CYP102A1
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Tenatoprazole, a proton pump inhibitor drug candidate, is developed as an acid inhibitor to treat gastric acid hypersecretion disorders, such as gastric ulcer and reflux esophagitis. Tenatoprazole is known to be metabolized to three major metabolites—tenatoprazole sulfone, 5’-hydroxylated metabolite, and tenatoprazole sulfide—in human livers mainly by CYP2C19 and CYP3A4. In this study, an enzymatic strategy for the production of human metabolites of tenatoprazole was developed using bacterial P450 enzymes. A set of CYP102A1 mutants catalyzed the regioselective hydroxylation reactions of tenatoprazole. The major product of tenatoprazole by CYP102A1 is 5’-OH tenatoprazole, a major human metabolite produced by human CYP2C19 and CYP3A4. As another major metabolite of tenatoprazole, tenatoprazole sulfide is formed via a non-enzymatic conversion without a P450 system. In addition, 5’-OH tenatoprazole sulfide was found as a minor metabolite, which can be formed via a 5’-hydroxylation reaction of tenatoprazole sulfide by CYP102A1 and/or a non-enzymatic reduction of 5’-OH tenatoprazole to a sulfide form. Chemical synthesis of the 5’-OH tenatoprazole is not currently possible. In conclusion, an enzymatic synthesis of 5’-OH tenatoprazole, a major human metabolite of tenatoprazole, was developed by using mutants of CYP102A1 from Bacillus megaterium as a biocatalyst and tenatoprazole as a substrate.
- Le, Thien-Kim,Cha, Gun-Su,Jang, Hyun-Hee,Nguyen, Thi Huong Ha,Doan, Tiep Thi My,Lee, Young Ju,Park, Ki Deok,Shin, Yumi,Kim, Dong-Hyun,Yun, Chul-Ho
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- tenatoprazole metabolites and preparation method thereof
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The present invention relates to 5andprime;-hydroxyl tenatoprazole and 5andprime;-hydroxyl tenatoprazole sulfide, which are novel metabolites of tenatoprazole, and a wild-type CYP102A1 mutant for producing the same. According to the present invention, 5andprime;-hydroxyl tenatoprazole and 5andprime;-hydroxyl tenatoprazole sulfide can be selectively produced in a massive amount by oxidizing tenatoprazole by using a point mutant of a wild-type CYP102A1 which is bacterial cytochrome P450 enzyme, chimera CYP102A1 prepared by fusing a heme domain of a point mutant of the wild-type CYP102A1 and a reducing enzyme of a natural mutant of the wild-type CYP102A1, and a point mutant of chimera CYP102A1 as enzymes.(AA) Tenatoprazole sulfide (known metabolome)COPYRIGHT KIPO 2019
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Paragraph 0089-0093; 0116; 0117
(2019/06/11)
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- An improved synthesis of antiulcerative drug: Tenatoprazole
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An efficient, cost-effective and multikilogram-scale process for the synthesis of tenatoprazole 1, an antiulcerative drug, is described. The key steps in this synthesis involve the coupling of 2-mercapto-5-methoxyimidazo[4,5- b]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 to yield 4 and its subsequent oxidation with m-CPBA to produce sulfoxide 1. The process has been scaled up for the multikilogram-scale of compound 1 with an overall yield of 72%. The new process requires no purification process and affords the target compound 1 with 99.8% purity by HPLC.
- Sripathi, Somaiah,Bojja, Ramachandra Reddy,Karnati, Venugopal Reddy,Prasada Raju,Khunt, Mayur D.
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experimental part
p. 804 - 806
(2010/04/22)
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- Synthesis and characterization of metabolites and potential impurities of the antiulcerative drug tenatoprazole
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Tenatoprazole (Ulsacare) is a recently developed antiulcerative drug used for the treatment of both erosive and nonerosive gastroesophageal reflux disease. During the bulk synthesis of tenatoprazole, we have observed four impurities (tenatoprazole N-oxide, tenatoprazole sulfone N-oxide, N-methyl tenatoprazole, and desmethoxy tenatoprazole) and two metabolites (tenatoprazole sulfide and tenatoprazole sulfone). The present work describes the synthesis and characterization of these impurities. Copyright Taylor & Francis Group, LLC.
- Reddy, Ganta Madhusudhan,Prasada Raju,Babu, J. Moses,Praveen,Khunt, Mayur,Mukkanti,Pratap Reddy, Padi
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p. 1725 - 1736
(2008/09/20)
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- Improved synthetic approach to tenatoprazole
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An improved synthetic approach to tenatoprazole 1 is described. It started from 2,3,5-trimethyl-4-nitropyridine-N-oxide 2 with acetic anhydride via rearrangement and hydrolysis to give 3, Chlorination with SOCl2 yielded 2-chloromethyl-3,5-dimethyl-4-nitropyridine hydrochloride 4, then 4 condensed with 2-mercapto-5-methoxy imidazole [4,5-b]pyridine 5 to give 5-methoxy-2-[(4-nitro-3,5-dimethyl-2-pyridinyl)methylthio]imidazole[4,5-b] pyridine 6. At last the title compound 1 was produced by two methods: 6 was oxidized with MCPBA and then methoxylated with CH3ONa to give 1 and 6 was first methoxylated with CH3ONa and then oxidized with MCPBA to give 1. The overall yield is around 26% for both five-step syntheses. Copyright Taylor & Francis Group, LLC.
- Dai, Liyan,Fan, Dongbo,Wang, Xiaozhong,Chen, Yingqi
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p. 576 - 582
(2008/04/12)
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