ChemInform Abstract: Synthesis and Pharmacological Activity of Stereoisomers of 1,4‐Dihydro‐2,6‐dimethyl‐4‐(3‐nitrophenyl)‐3,5‐pyridinedicarboxylic Acid Methyl 1‐(Phenylmethyl)‐3‐piperidinyl Ester.

Muto, K; Kuroda, Toshio; Kawato, Haruko C.; Karasawa, Akira; Kubo, Kazuhiro; Nakamizo, Nobuhiro

doi:10.1002/chin.198918215

Cited by 6 publications

(10 citation statements)

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“…Because the hepatic intrinsic clearance rate for (−)-alpha benidipine is greater than that for (+)-alpha benidipine, plasma concentrations of (+)-alpha benidipine are greater than those of (−)-alpha benidipine following the administration of a benidipine racemate to rats [5]. In addition, the hypotensive effect of (+)-alpha benidipine was between 30-and 100-fold the effect of (−)-alpha benidipine in spontaneously hypertensive rats [1]. The aforementioned observations suggest that the competitive metabolism of the stereoisomers of benidipine that follows the oral administration of the benidipine racemate gives rise to differential pharmacokinetics for the different enantiomers of benidipine.…”

Section: Introductionmentioning

confidence: 85%

“…In animal studies, the kinetic behavior and dynamic efficacies, respectively, of the benidipine stereoisomers were different [1][2][3][4]. Because the hepatic intrinsic clearance rate for (−)-alpha benidipine is greater than that for (+)-alpha benidipine, plasma concentrations of (+)-alpha benidipine are greater than those of (−)-alpha benidipine following the administration of a benidipine racemate to rats [5].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of benidipine enantiomers in human plasma by liquid chromatography–mass spectrometry using a macrocyclic antibiotic (Vancomycin) chiral stationary phase column

Kang¹,

Lee²,

Liu³

et al. 2005

Journal of Chromatography B

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Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Analysis of benidipine enantiomers in human plasma by liquid chromatography–mass spectrometry using a macrocyclic antibiotic (Vancomycin) chiral stationary phase column

Kang¹,

Lee²,

Liu³

et al. 2005

Journal of Chromatography B

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“…Benidipine, (S, S)-benidipine, (R, R)-benidipine, and amlodipine were synthesized in our laboratories as described (Arrowsmith et al, 1986;Muto et al, 1988). Efonidipine was extracted from tablets (Zeria, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Mechanism underlying the block of human Cav3.2 T-type Ca2+ channels by benidipine, a dihydropyridine Ca2+ channel blocker

et al. 2011

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mentioning

confidence: 98%

“…The (ϩ)-␣ isomer was 30-to 100-fold more active than the (Ϫ)-␣ isomer in terms of the antihypertensive effect after i.v. administration to the spontaneously hypertensive rat (Muto et al, 1988).Pharmacokinetic studies in rats (Kobayashi and Kobayashi, 1998) and humans (Kobayashi et al, 1997) have shown that benidipine is well absorbed but exhibits low absolute bioavailability as a result of marked first-pass metabolism. Accordingly, various metabolites were identified in these species (Kobayashi et al, 1997;Kobayashi and Kobayashi, 1998).…”

mentioning

confidence: 99%

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

Yoon¹,

Kim²,

Kim³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Benidipine is a dihydropyridine calcium antagonist that has been used clinically as an antihypertensive and antianginal agent. It is used clinically as a racemate, containing the (؊)-␣ and (؉)-␣ isomers of benidipine. This study was performed to elucidate the metabolism of benidipine and its enantiomers in human liver microsomes (HLMs) and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of benidipine. Human liver microsomal incubation of benidipine in the presence of NADPH resulted in the formation of two metabolites, N-desbenzylbenidipine and dehydrobenidipine. The intrinsic clearance (CL int ) of the formation of N-desbenzylbenidipine and dehydrobenidipine metabolites from (؊)-␣ isomer was similar to those from the (؉)-␣ isomer (1.9 ؎ 0.1 versus 2.3 ؎ 2.3 l/min/pmol P450 and 0.5 ؎ 0.2 versus 0.6 ؎ 0.6 l/min/pmol P450, respectively). Correlation analysis between the known P450 enzyme activities and the rate of the formation of benidipine metabolites in the 15 HLMs showed that benidipine metabolism is correlated with CYP3A activity. The P450 isoform-selective inhibition study in liver microsomes and the incubation study of cDNA-expressed enzymes also showed that the N-debenzylation and dehydrogenation of benidipine are mainly mediated by CYP3A4 and CYP3A5. The total CL int values of CYP3A4-mediated metabolite formation from (؊)-␣ isomer were similar to those from (؉)-␣ isomer (17.7 versus 14.4 l/min/pmol P450, respectively). The total CL int values of CYP3A5-mediated metabolite formation from (؊)-␣ isomer were also similar to those from (؉)-␣ isomer (8.3 versus 11.0 l/min/pmol P450, respectively). These findings suggest that CYP3A4 and CYP3A5 isoforms are major enzymes contributing to the disposition of benidipine, but stereoselective disposition of benidipine in vivo may be influenced not by stereoselective metabolism but by other factors.Benidipine is a highly potent dihydropyridine calcium antagonist that is used clinically as a racemate. This agent shows slow onset and long-lasting antihypertensive and antianginal effects owing to the blockade of calcium ion entry to smooth muscle Yamada et al., 1990). It is currently in clinical use for the treatment of hypertension as a single daily medication (2-8 mg). Like other dihydropyridine calcium antagonists (except nifedipine and mepirodipine), benidipine has asymmetric carbons both in the 1,4-dihydropyridine ring and in the side chain of the benzylpiperidine ring. This drug is a racemate consisting of two optical isomers [(ϩ)-␣ and (Ϫ)-␣ isomer] of the four possible optical isomers because the other isomers are removed during the crystallization step on synthesis (Kobayashi and Kobayashi, 1998). The (ϩ)-␣ isomer was 30-to 100-fold more active than the (Ϫ)-␣ isomer in terms of the antihypertensive effect after i.v. administration to the spontaneously hypertensive rat (Muto et al., 1988).Pharmacokinetic studies in rats (Kobayashi and Kobayashi, 1998) and humans (Kobayashi et al., 1997) have shown that benidipine is we...

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ChemInform Abstract: Synthesis and Pharmacological Activity of Stereoisomers of 1,4‐Dihydro‐2,6‐dimethyl‐4‐(3‐nitrophenyl)‐3,5‐pyridinedicarboxylic Acid Methyl 1‐(Phenylmethyl)‐3‐piperidinyl Ester.

Abstract: Esterification of the dihydropyridinedicarboxylic acid monoester (I) via the intermediate acid chloride with the piperidinol (II) gives the four diastereomers (III) ‐ (VI).

Cited by 6 publications

References 0 publications

Analysis of benidipine enantiomers in human plasma by liquid chromatography–mass spectrometry using a macrocyclic antibiotic (Vancomycin) chiral stationary phase column

Analysis of benidipine enantiomers in human plasma by liquid chromatography–mass spectrometry using a macrocyclic antibiotic (Vancomycin) chiral stationary phase column

Mechanism underlying the block of human Cav3.2 T-type Ca2+ channels by benidipine, a dihydropyridine Ca2+ channel blocker

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

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