Role of racemization in optically active drugs development

Ali, Imran; Gupta, Vinod K.; Aboul‐Enein, Hassan Y.; Singh, Prashant; Sharma, Bhuvanesh Kumar

doi:10.1002/chir.20397

Cited by 100 publications

(70 citation statements)

References 100 publications

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“…Racemization is a particular problem because its detection requires chiral analytical methods 13, 14. Hence, few reports disclose rate constants for racemization under aqueous conditions 1, 15, 16, 17, 18, 19, 20.…”

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Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

et al. 2017

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Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

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“…13 The interaction of two enantiomers of a chiral drug with metabolizing enzyme brings about two diastereomeric states of different probabilities. This enantioselective recognition may result in different pharmaceutical activities.…”

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Pharmacokinetics of nateglinide enantiomers and their metabolites in Goto‐Kakizaki rats, a model for type 2 diabetes mellitus

et al. 2009

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The pharmacokinetics of (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) and its enantiomer (L-enantiomer) was studied in Goto-Kakizaki (GK) rats after intravenous administration of nateglinide or L-enantiomer at a dose of 40 micromol/kg body weight. Nateglinide, its L-enantiomer and their metabolites in serum, bile and urine were determined. The total clearance (CL(tot)) and the volume of distribution (Vd) was slightly higher for nateglinide than those for L-enantiomer in control rats, although the differences were not statistically significant. The cumulative excretions of L-M1 (major metabolite of L-enantiomer) and L-M2 (major metabolite of L-enantiomer) into bile were almost the same as that of M1 (major metabolite of nateglinide)and M2 (major metabolite of nateglinide). In GK rats, CL(tot) and Vd were higher for nateglinide than those for L-enantiomer. The cumulative excretion of L-M1 and L-M2 were not different from those of M1 and M2, respectively, into bile or urine. CL(tot) and Vd for nateglinide or L-enantiomer in GK rats were not different from those in control rats. The total excretion of M1, M2, L-M1, and L-M2 into bile or urine in GK rats was not substantially different from that of control rats. These results suggest that the L-enantiomer of nateglinide shows higher CL(tot) and Vd compared with nateglinide, especially in the diabetic state.

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“…[13,14] Hence,f ew reports disclose rate constants for racemization under aqueous conditions. [1,[15][16][17][18][19][20] Chiral centers with certain combinations of substituents have been posited to be prone to general-basecatalyzed racemization although with little supporting data.…”

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Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

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Racemization has alarge impact upon the biological properties of molecules but the chemical scope of compounds with knownr ate constants for racemization in aqueous conditions was hitherto limited. To address this remarkable blind spot, we have measured the kinetics for racemization of 28 compounds using circular dichroism and 1 HNMR spectroscopy. We show that rate constants for racemization (measured by ourselves and others) correlate well with deprotonation energies from quantum mechanical (QM) and group contribution calculations.Such calculations thus provide predictions of the second-order rate constants for general-basecatalyzedr acemization that are usefully accurate.W hen applied to recent publications describing the stereoselective synthesis of compounds of purported biological value,t he calculations reveal that racemization would be sufficiently fast to render these expensive syntheses pointless.Thalidomide racemizes in am atter of hours and yet it remains ap oster child for enantioselective synthesis which would not have saved its victims.[1] Thes tatus quo in enantioselective synthesis thus ignores the cruel blind spot that we address in this paper:racemization.Although necessary in dynamic kinetic resolution protocols, [2,3] racemization and epimerization can caus es afe compounds to become toxic or lose efficacy, [4][5][6][7][8][9][10][11] lead to misidentification of chiral compounds extracted from natural sources, [12] etc.I gnoring racemization thus leads to wasted material and human resources.Racemization is ap articular problem because its detection requires chiral analytical methods. [13,14] Hence,f ew reports disclose rate constants for racemization under aqueous conditions. [1,[15][16][17][18][19][20] Chiral centers with certain combinations of substituents have been posited to be prone to general-basecatalyzed racemization although with little supporting data. [21][22][23] We therefore classified stereogenic carbon atoms according to their attached substituents.E ach substituent is identified as one of sixty types, [24] which encompass more than 99.95 %ofall such substituents in the GOSTAR database. [25] Thet en most frequently occurring substituents are listed in Figure 1; the Hr equired for general-base-catalyzed racemization is prominent.[24] Groups labelled *w ere selected for experimental study.Based on prevalence,e arlier work, [21][22][23] and chemical intuition, several compounds were selected for detailed kinetic studies. [26][27][28] Ther ate constants for general-basecatalyzed racemization were derived for ar ange of 11 arylglycine derivatives (1, 2 and 3), 12 hydantoins (4, 5 and 6)a nd 5t hiohydantoins (7 and 8). Briefly,a ts everal buffer concentrations,c ircular dichroism spectroscopy (CD) followed the decrease in ellipticity and/or 1 HNMR spectroscopy the incorporation of Dfrom deuterated buffers.T he pseudo- first-order rate constants for these processes were corrected for hydrolysis side reactions if required. [24] Plotting the firstorder rate constants for ...

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Role of racemization in optically active drugs development

Cited by 100 publications

References 100 publications

Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

Pharmacokinetics of nateglinide enantiomers and their metabolites in Goto‐Kakizaki rats, a model for type 2 diabetes mellitus

Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

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