- Development and validation of different methods manipulating zero order and first order spectra for determination of the partially overlapped mixture benazepril and amlodipine: A comparative study
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Three simple, selective, and accurate spectrophotometric methods have been developed and then validated for the analysis of Benazepril (BENZ) and Amlodipine (AML) in bulk powder and pharmaceutical dosage form. The first method is the absorption factor (AF
- Hemdan
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- Optimal pH 8.5 to 9 for the hydrolysis of vixotrigine and other basic substrates of carboxylesterase-1 in human liver microsomes
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Vixotrigine is a voltage- and use-dependent sodium channel blocker under investigation for the potential treatment of neuropathic pain. One of the major in?vivo metabolic pathways of vixotrigine in humans is the hydrolysis of the carboxamide to form the carboxylic acid metabolite M14. The in?vitro formation of M14 in human hepatocytes was inhibited by the carboxylesterase (CES) inhibitor Bis(4-nitrophenyl) phosphate in a concentration-dependent manner. The hydrolysis reaction was identified to be catalysed by recombinant human CES1b. Initial observation of only trace level formation of M14 in human liver microsomes at pH 7.4 caused us to doubt the involvement of CES1, an enzyme localised at the endoplasmic reticulum and the dominant carboxylesterase in human liver. Further investigation has revealed that optimal pH for the hydrolysis of vixotrigine and two other basic substrates of CES1, methylphenidate and oseltamivir, in human liver microsomes was pH 8.5–9 which is higher than their respective pKa(base), suggesting that neutral form of basic substrates is probably preferred for CES1 catalysis in liver microsomes.
- Gu, Chungang,Huang, Jiansheng,Johnson, Joshua L.,Rooney, Michael
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- Hydrolytic profile for ester- or amide-linkage by carboxylesterases pI 5.3 and 4.5 from human liver
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Carboxylesterases (EC 3.1.1.1) from human liver were purified using Q- Sepharose, Sephadex G-150, isoelectrofocusing and Con A-Sepharose. The calculated molecular mass of the pI 5.3 enzyme was 120 kDa and 61 kDa from the results of Sephadex G-150 gel filtration and SDS-polyacrylamide gel electrophoresis (PAGE), respectively, suggesting that this enzyme is a dimer. On the other hand, carboxylesterase pI 4.5, with a molecular-mass of 64 kDa, was a monomer. The activities of both enzymes were inhibited by typical serine enzyme inhibitors. Amino acid sequence analysis of the purified enzymes pI 5.3 and 4.5 showed high homology with rabbit carboxylesterase form 1 and 2, respectively. The results also suggested that carboxylesterase pI 5.3 is identical to the deduced amino acid sequence from cDNA for HUI, and that carboxylesterase pI 4.5 is identical to the deduced amino acid sequence from the cDNA registered as human carboxylesterase (hCE-2) in GenBank. We first purified carboxylesterase pI 4.5 and investigated its hydrolytic activity upon various drugs. The two enzymes differed in substrate specificity. Prodrugs of angiotensin-converting enzyme inhibitors, such as delapril and imidapril, were converted to active metabolites by carboxylesterase pI 5.3, but not by carboxylesterase pI 4.5. The hydrolysis velocity of temocapril by carboxylesterase pI 5.3 was 12-fold faster than by carboxylesterase pI 4.5. In contrast, aspirin oxybutynin and procaine were hydrolyzed by only carboxylesterase pI 4.5. We also found that an amide- linkage in drugs, except for that in aniracetam was not a good substrate for the two enzymes. Consequently, carboxylesterases pI 5.3 and 4.5 maybe involved in the metabolism of various drugs containing an ester-linkage.
- Takai, Satomi,Matsuda, Ayuka,Usami, Yoshiko,Adachi, Tetsuo,Sugiyama, Tadashi,Katagiri, Yoshihiro,Tatematsu, Masae,Hirano, Kazuyuki
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p. 869 - 873
(2007/10/03)
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- 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids
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Variously substituted 1-carboxymethyl-3-(carboxymethylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-ones and functional derivatives are angiotensin converting enzyme inhibitors and are useful as antihypertensive agents. Synthesis of, compositions and methods of treatment utilizing such compounds are included.
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- Synthesis and biological properties of (carboxyalkyl)amino-substituted bicyclic lactam inhibitors of angiotensin converting enzyme
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Syntheses of the potent angiotensin converting enzyme inhibitor (3S)-1-(carboxymethyl)-3-[[(1S)-1-carboxy-3-phenylpropyl]amino]-2,3,4,5 -tetrahydro-1H-[1]benzazepin-2-one (CGS 14831) and the related monoester prodrug (17a; CGS 14824A) are described together with preparative details for six- and eight-membered ring analogues. Inhibitory potencies and in vivo biological activity of the compounds are discussed. The data indicate that 17a has a biological profile comparable to that of enalapril.
- Watthey,Stanton,Desai,Babiarz,Finn
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p. 1511 - 1516
(2007/10/02)
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- 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids
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Variously substituted 1-carboxymethyl-3-(carboxymethylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-ones and functional derivatives are angiotension converting enzyme inhibitors and are useful as antihypertensive agents. Synthesis of, compositions and methods of treatment utilizing such compounds are included.
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