Stereoselectivity of bioactive xenobiotics

Ariëns, E. J.; Wuis, E.W.; Veringa, Eric J.

doi:10.1016/0006-2952(88)90749-6

Cited by 137 publications

(39 citation statements)

References 21 publications

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“…However, factors such as phar- macokinetic properties, namely differential uptake, transport, metabolism, or protein binding may be the cause of the stereoselectivity observed for a set of isomers. 21 The use of in vitro systems eliminates considerations such as tissue uptake and distribution. It is possible that the stereoselective effects observed in response to our CPPA isomers are due to pharmacokinetic events other than the interaction of the ligand molecule with the receptor.…”

Section: Discussionmentioning

confidence: 99%

Stereoselective effects of chiral clofibric acid analogs on rat peroxisome proliferator-activated receptor ? (rPPAR?) activation and peroxisomal fatty acid ?-oxidation

et al. 1997

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Enantiomers of a series of substituted analogs of 2‐(4‐chloronhenoxy)‐acetic acid (CPAA) were synthesized and used to examine the influence of steric and structural parameters on peroxisome proliferation. The effects of these compounds were studied on the activation of the peroxisome proliferator‐activated receptor α (PPARα) in CV‐1 cells using an in vitro co‐transfection assay. Selected sets of isomers were tested for their ability to increase peroxisomal fatty acyl‐CoA oxidase (ACO) activity in H4IIEC3 (rat Reuber hepatoma) cells. Of the series of 2‐substituted analogs studied, the isomers of the n‐propyl and phenyl derivatives of CPAA showed a high degree of stereoselectivity [(S)‐isomer ≫ (R)‐isomer]. In general, the potency of the compound to activate the receptor increased with the size of the 2‐alkyl substituent. Among the 4‐chlorobenzyloxy‐ and 4‐(4′‐chlorophenyl)benzyloxy‐ analogs studied, 2‐[4‐(4′‐chlorophenyl)‐benzyloxy]‐propanoic acid exhibited a high degree of stereoselectivity in both the biological systems studied [(R) ≫ (S)]. The congeners of 2‐methyl substituted CPAA showed a reverse stereoselectivity [(R) > (S)] as compared to the other 2‐substituted analogs [(S) > (R)]. Our results indicate that (1) both structural and steric characteristics of CPAA analogs play an important role in the activation of rPPARα and on stimulation of peroxisomal ACO activities, and (2) clofibric acid and analogs exert their peroxisome proliferative effects by interaction with a specific site on a protein. The enantiomers of the 2‐n‐propyl and the 2‐phenyl CPAA analogs may be useful as mechanistic probes in elucidating the nature of this binding site. Chirality 9:37–47, 1997. © 1997 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Stereoselective effects of chiral clofibric acid analogs on rat peroxisome proliferator-activated receptor ? (rPPAR?) activation and peroxisomal fatty acid ?-oxidation

et al. 1997

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“…In recent years, considerable dispute has arisen about the advantage of administering therapeutic agents as single isomers [1][2][3][4]. Optical antipodes of many drugs, in fact, have been proven to display different degrees of activity and toxicity [5,6].…”

Section: Introductionmentioning

confidence: 99%

LFER and CoMFA studies on optical resolution of ?-alkyl ?-aryloxy acetic acid methyl esters on DACH-DNB chiral stationary phase

Carotti

Altomare

Cellamare

et al. 1995

J Computer-Aided Mol Des

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The HPLC resolution of a series of racemic alpha-substituted alpha-aryloxy acetic acid methyl esters I on a pi-acid N,N'-(3,5-dinitrobenzoyl)-trans-1,2-diaminocyclohexane as chiral selector was modelled by linear free energy-related (LFER) equations and comparative molecular field analysis (CoMFA). Our results indicate that the retention process mainly depends on solute lipophilicity and steric properties, whereas enantioselectivity is primarily influenced by electrostatic and steric interactions. CoMFA provided additional information with respect to the LFER study, allowed the mixing of different subsets of I and led to a quantitative 3D model of steric and electrostatic factors responsible for chiral recognition.

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“…Using the S-enantiomer would lead to relatively strong [3-blockade with only a weak vasodilating effect. The R-enantiomer alone would act only as a hypotensive agent without [3-blockade.Key words: stereoisomers, c~-blockade, [3-blockade, carvedilol The pharmacological profile of carvedilol in animals as well as in man has been published in various papers [1][2][3].Stereoselectivity of drugs is arousing increasing attention [4,5], in particular in cases where there is more than one pharmacological effect. The importance of stereoselectivity becomes clearer if it is considered that each drug, apart from its main pharmacological quality, has to be characterized regarding pharmacokinetics, metabolism and, in particular, safety.…”

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confidence: 99%

Pharmacological characteristics of the stereoisomers of carvedilol

Bartsch¹,

Sponer²,

Strein³

et al. 1990

Eur J Clin Pharmacol

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The racemic compound carvedilol possesses two complementary pharmacological effects, vasodilation and beta-blockade. The R- and S-enantiomers of carvedilol and the racemate were investigated with respect to the beta-blocking, vasodilating, and hypotensive actions. In agreement with results obtained with other beta-blockers, only the S-enantiomer of carvedilol exerts beta-blocking effects. In contrast, no substantial difference between the enantiomers could be seen with respect to alpha-blockade. The greater hypotensive activity of S-carvedilol may be attributed to beta-blockade, which inhibits counter-regulatory mechanisms provoked by vasodilation. From these results it is concluded that there is a rationale for using carvedilol as the racemate. Using the S-enantiomer would lead to relatively strong beta-blockade with only a weak vasodilating effect. The R-enantiomer alone would act only as a hypotensive agent without beta-blockade.

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Stereoselectivity of bioactive xenobiotics

Cited by 137 publications

References 21 publications

Stereoselective effects of chiral clofibric acid analogs on rat peroxisome proliferator-activated receptor ? (rPPAR?) activation and peroxisomal fatty acid ?-oxidation

Stereoselective effects of chiral clofibric acid analogs on rat peroxisome proliferator-activated receptor ? (rPPAR?) activation and peroxisomal fatty acid ?-oxidation

LFER and CoMFA studies on optical resolution of ?-alkyl ?-aryloxy acetic acid methyl esters on DACH-DNB chiral stationary phase

Pharmacological characteristics of the stereoisomers of carvedilol

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