Rapid Racemization in Thiazolidinediones:  A Quantum Chemical Study

Bharatam, Prasad V.; Khanna, Smriti

doi:10.1021/jp0366522

Cited by 30 publications

(20 citation statements)

References 45 publications

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“…Recently, S‐oxidation has been proposed to render TZD racemization more thermodynamically and kinetically favorable 20. However, it is unlikely that S‐oxidation is involved in the racemization of MK‐0767, since it was shown to proceed readily in plasma.…”

Section: Resultsmentioning

confidence: 99%

Enantiomer ratio of MK‐0767 in humans and nonclinical species

Shen

Bakhtiar

Komuro

et al. 2005

Rapid Comm Mass Spectrometry

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MK-0767, (+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]methyl]benzamide, is a thiazolidinedione-containing dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist that has been studied as a potential treatment for patients with type 2 diabetes. MK-0767 contains a chiral center at the C-5 position of the thiazolidinedione ring and was being developed as the racemate, due to the rapid interconversion of its enantiomers in biological samples. In the present work the in vitro and in vivo concentration ratios of the (+)-(R) to (-)-(S) enantiomers of MK-0767 were determined in plasma from humans (in vitro only) and nonclinical species used in the toxicological evaluation of rac-MK-0767, namely CD-1 mice, Sprague-Dawley rats, beagle dogs, New Zealand white rabbits, and rhesus monkeys. The R/S ratio was determined by chiral liquid chromatography/tandem mass spectrometry. Species differences were observed in the in vitro and in vivo enantiomeric ratios, as well as differences between in vitro and in vivo in some species. The in vitro R/S ratio was similar in dogs and humans (approximately 1.5-1.7). In rats and monkeys, the ratio was approximately unity, both in vitro and in vivo. In mice, the ratio was higher in vitro (approximately 1) than in vivo (approximately 0.6), while in rabbits it was higher in vivo (approximately 1) than in vitro (approximately 0.5). These results suggested that differential binding of the MK-0767 enantiomers to plasma and tissue proteins and other macromolecules may be affecting the R/S ratio both in vitro and in vivo, since in protein-free systems MK-0767 exists as the racemate.

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Section: Resultsmentioning

confidence: 99%

Enantiomer ratio of MK‐0767 in humans and nonclinical species

Shen

Bakhtiar

Komuro

et al. 2005

Rapid Comm Mass Spectrometry

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“…The energy difference between acetaldehyde and vinylalcohol is reported to be of the order of 16 kcal/mol, 56 it is generally considered that any keto-enol pair whose energy difference is less than 16 kcal/mol is a feasible tautomerisation process. [57][58][59] In compound 1, the keto-enol energy difference (i.e. ∆G between 1 and 3) is estimated to be 11.3 kcal/mol, thus indicating that ketoenol tautomersim is an accessible process in 1,4-diketones.…”

Section: Monoenol Pathwaymentioning

confidence: 99%

Mechanism of the Paal–Knorr reaction: the importance of water mediated hemialcohol pathway

et al. 2015

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The Paal-Knorr synthesis of furan, pyrrole and thiophene rings is one of the most important methods of generating these very important heterocycles, but the mechanism of this reaction is not well understood. Though several mechanistic paths are suggested, the exact energy requirements of this reaction, the structural features of transition states associated with the cyclization step, have not been established, especially for furan and thiophene synthesis. In this work, we explore the mechanism of the Paal-Knorr method and establish the energy requirements, using quantum chemical methods. The Paal-Knorr reaction to give furans is endergonic by 3.7 kcal/mol whereas the same reaction is exergonic for pyrrole and thiophene generation by 16.4 and 15.9 kcal/mol, using G2MP2 method. The cyclization step is associated with high energy barrier, however, explicit water participation reduces the barrier significantly. For example, under the neutral condition two water mediated pathways -(i) monoenol and (ii) hemiketal, are possible on the reaction leading to furan. The cyclization step in these two pathways require 28.9 and 27.1 kcal/mol, respectively. The ring formation step becomes highly favorable in the presence of H3O + with a barrier of only 11.5 kcal/mol (solvent phase) from the monoenol to dihydrofuran derivative and 5.5 kcal/mol (solvent phase) from hemiketal to dihydroxy dihydrofuran derivative. Similarly, a water mediated pathway involving the intermediacy of hemialcohols has been found to be energetically preferred mechanism for pyrrole and thiophene also.

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“…Racemization in the TZD class of compounds has been well established by both experimental [121] and theoretical studies [122]. Bharatam and Khanna performed theoretical studies and proposed the importance of S-oxidation in the rapid racemization of TZD class of drugs [122]. Thus, due to this racemization administration of a pure enantiomer was not considered for this class of drugs.…”

Section: Reddy Et Al Reported Benzyloxy Derivatives Of Tgzmentioning

confidence: 99%

SAR and Computer-Aided Drug Design Approaches in the Discovery of Peroxisome Proliferator-Activated Receptor γ Activators: A Perspective

Dixit

Bharatam

2013

Journal of Computational Medicine

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Activators of PPARγ, Troglitazone (TGZ), Rosiglitazone (RGZ), and Pioglitazone (PGZ) were introduced for treatment of Type 2 diabetes, but TGZ and RGZ have been withdrawn from the market along with other promising leads due cardiovascular side effects and hepatotoxicity. However, the continuously improving understanding of the structure/function of PPARγand its interactions with potential ligands maintain the importance of PPARγas an antidiabetic target. Extensive structure activity relationship (SAR) studies have thus been performed on a variety of structural scaffolds by various research groups. Computer-aided drug discovery (CADD) approaches have also played a vital role in the search and optimization of potential lead compounds. This paper focuses on these approaches adopted for the discovery of PPARγligands for the treatment of Type 2 diabetes. Key concepts employed during the discovery phase, classification based on agonistic character, applications of various QSAR, pharmacophore mapping, virtual screening, molecular docking, and molecular dynamics studies are highlighted. Molecular level analysis of the dynamic nature of ligand-receptor interaction is presented for the future design of ligands with better potency and safety profiles. Recently identified mechanism of inhibition of phosphorylation of PPARγat SER273 by ligands is reviewed as a new strategy to identify novel drug candidates.

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Rapid Racemization in Thiazolidinediones: A Quantum Chemical Study

Cited by 30 publications

References 45 publications

Enantiomer ratio of MK‐0767 in humans and nonclinical species

Enantiomer ratio of MK‐0767 in humans and nonclinical species

Mechanism of the Paal–Knorr reaction: the importance of water mediated hemialcohol pathway

SAR and Computer-Aided Drug Design Approaches in the Discovery of Peroxisome Proliferator-Activated Receptor γ Activators: A Perspective

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