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Chiral Drugs (chiral + drug)
Selected AbstractsCaptopril and its synthesis from chiral intermediatesJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 2 2001R Chirumamilla Abstract Captopril is an antihypertensive agent that inhibits the angiotensin-converting enzyme of the renin,angiotensin system. Chiral intermediates are used in the synthesis of the drug. These intermediates are obtained by resolution of racemic compounds or by chemical, biocatalytic methods and or by asymmetric synthesis by biocatalytic process. This article reviews the various chemical and biochemical processes involved in the synthesis of the chiral drug, including the pharmacological action of captopril. © 2001 Society of Chemical Industry [source] Chiral analysis of milnacipran by a nonchiral HPLC , circular dichroism: Improvement of the linearity of dichroic response by temperature controlJOURNAL OF SEPARATION SCIENCE, JSS, Issue 16-17 2008Marie Lecoeur-Lorin Abstract The determination of the enantiomeric excess (e.e.) of a basic drug has been investigated in LC using a nonchiral stationary phase and a circular dichroism (CD) detector in order to avoid expensive chiral columns. The CD detector records both dichroic (,,) and UV (,) signals at the same wavelength and calculates the anisotropy factor (g = ,,/,), which is linearly related to the e.e. The enantiomeric and chemical composition of a chiral drug can be simultaneously determined on a nonchiral HPLC support. However, the g factor from the CD signal is temperature dependent. Indeed, the temperature has an influence on the stability of the CD signal and the linear regression between g factor and the e.e. of 1R,2S -enantiomer. So, a decrease in temperature gives rise to an improvement of the above-mentioned linearity correlation. After optimization of chromatographic parameters (porous graphitic carbon-based column, methanol/ phosphate buffer as mobile phase) and selection of CD wavelength, a linear regression of g factor versus e.e. of 1R,2S -enantiomer was obtained at temperature-controlled CD detection and an LOQ of 94% was found. The enantiomeric composition of milnacipran was determined with good accuracy. [source] Microseparation techniques for the study of the enantioselectivity of drug,plasma protein bindingBIOMEDICAL CHROMATOGRAPHY, Issue 3 2009Laura Escuder-Gilabert Abstract Stereoselectivity in protein binding can have a significant effect on the pharmacokinetic and pharmacodynamic properties of chiral drugs. The investigation of enantioselectivity of drugs in their binding with human plasma proteins and the identification of the molecular mechanisms involved in the stereodiscrimination by the proteins represent a great challenge for clinical pharmacology. In this review, the separation techniques used for enantioselective protein binding experiments are described and compared. An overview of studies on enantiomer,protein interactions, enantiomer,enantiomer interactions as well as chiral drug,drug interactions, including allosteric effects, is presented. The contribution of individual plasma proteins to the overall enantioselective binding and the animal species variability in drug,plasma protein binding stereoselectivity are reviewed. Copyright © 2008 John Wiley & Sons, Ltd. [source] Evaluation of enantioselective binding of antihistamines to human serum albumin by ACEELECTROPHORESIS, Issue 15 2007María Amparo Martínez-Gómez Abstract The drug binding to plasma and tissue proteins is a fundamental factor in determining the overall pharmacological activity of a drug. HSA, together with ,1 -acid glycoprotein, are the most important plasma proteins, which act as drug carriers, with implications on the pharmacokinetic of drugs. Among plasma proteins, HSA possesses the highest enantioselectivity. In this paper, a new methodology for the study of enantiodifferentiation of chiral drugs with HSA is developed and applied to evaluate the possible enantioselective binding of four antihistamines: brompheniramine, chlorpheniramine, hydroxyzine and orphenadrine to HSA. This study includes the determination of affinity constants of drug enantiomers to HSA and the evaluation of the binding sites of antihistamines on the HSA molecule. The developed methodology includes the ultrafiltration of samples containing HSA and racemic antihistaminic drugs and the analysis of the free or bound drug fraction using the affinity EKC-partial filling technique and HSA as chiral selector. The results shown in this paper represent the first evidence of the enantioselective binding of antihistamines to HSA, the major plasmatic protein. [source] Application of polymeric surfactants in micellar electrokinetic chromatography-electrospray ionization mass spectrometry of benzodiazepines and benzoxazocine chiral drugsELECTROPHORESIS, Issue 5-6 2006Jingguo Hou Abstract Chiral micellar EKC (CMEKC) coupled to ESI-MS using polymeric surfactants as pseudostationary phases is investigated for simultaneous enantioseparation of two benzodiazepines, (±)-oxazepam ((±)-OXA) and (±)-lorazepam ((±)-LOR), and one benzoxazocine, (±)-nefopam ((±)-NEF). First, enantioselectivity and electrospray sensitivity of six chiral polymeric surfactants for all three chiral compounds are compared. Second, using poly(sodium N -undecenoyl- L -leucinate) as pseudostationary phase, the organic modifiers (methanol (MeOH), isopropanol, and ACN) are added into the running buffer to further improve chiral resolution (RS). Next, a CMEKC-ESI-MS method for the simultaneous enantioseparation of two benzodiazepines is further developed by using a dipeptide polymeric surfactant, poly(sodium N -undecenoxy carbonyl- L,L -leucyl-valinate) (poly- L,L -SUCLV). The CMEKC conditions including nebulizer pressure, capillary length, ammonium acetate concentration, pH, poly- L,L -SUCLV concentration, and capillary temperature were optimized to achieve maximum chiral RS and highest sensitivity of MS detection. The spray chamber parameters (drying gas temperature and drying gas flow rate) as well as sheath liquid conditions (MeOH content, pH, flow rate, and ionic strength) were found to significantly influence MS S/N of both (±)-OXA and (±)-LOR. Finally, a comparative study between simultaneous UV and MS detection showed high plate numbers, better chiral RS, and enhanced detectability with CMEKC-MS. However, speed of analysis was faster using CMEKC-UV. [source] Enantioseparation in capillary electrophoresis using 2- O -(2-hydroxybutyl)-,-CD as a chiral selectorELECTROPHORESIS, Issue 20 2005Xiuli Lin Abstract The resolving ability of 2- O -(2-hydroxybutyl)-,-CD (HB-,-CD) with different degrees of substitution (DS,=,2.9 and 4.0) as a chiral selector in CZE is reported in this work. Fourteen chiral drugs belonging to different classes of compounds of pharmaceutical interest such as ,-agonists, antifungal agents, ageneric agents, etc., were resolved. The effects of the DS of HB-,-CD on separations were also investigated. The chiral resolution (Rs) was strongly influenced by the concentrations of the CD derivative, the BGE, and the pH of the BGE. Under the conditions of 50,mmol/L Tris-phosphate buffer at pH,2.5 containing 5,mmol/L HB-,-CD, all 14 analytes were separated. The very low concentration necessary to obtain separation was particularly impressive. The DS had a significant effect on the resolution of the chiral drugs and the ionic strength of the separation media; hence, the use of a well-characterized CD derivative is crucial. [source] Bond-based 3D-chiral linear indices: Theory and QSAR applications to central chirality codificationJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 15 2008Juan A. Castillo-Garit Abstract The recently introduced non-stochastic and stochastic bond-based linear indices are been generalized to codify chemical structure information for chiral drugs, making use of a trigonometric 3D-chirality correction factor. These improved modified descriptors are applied to several well-known data sets to validate each one of them. Particularly, Cramer's steroid data set has become a benchmark for the assessment of novel quantitative structure activity relationship methods. This data set has been used by several researchers using 3D-QSAR approaches such as Comparative Molecular Field Analysis, Molecular Quantum Similarity Measures, Comparative Molecular Moment Analysis, E-state, Mapping Property Distributions of Molecular Surfaces, and so on. For that reason, it is selected by us for the sake of comparability. In addition, to evaluate the effectiveness of this novel approach in drug design we model the angiotensin-converting enzyme inhibitory activity of perindoprilate's ,-stereoisomers combinatorial library, as well as codify information related to a pharmacological property highly dependent on the molecular symmetry of a set of seven pairs of chiral N -alkylated 3-(3-hydroxyphenyl)-piperidines that bind ,-receptors. The validation of this method is achieved by comparison with earlier publications applied to the same data sets. The non-stochastic and stochastic bond-based 3D-chiral linear indices appear to provide a very interesting alternative to other more common 3D-QSAR descriptors. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008 [source] Chiral polymers for resolution of enantiomersJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 7 2009Yoshio Okamoto Abstract In 1979, the formation of one-handed helical poly(triphenylmethyl methacrylate) (PTrMA) was found through the helix-sense-selective polymerization of methacrylate using chiral anionic initiators, and the existence of a stable helical polymer without chiral side chains was proved. The chiral polymer exhibited unexpected high chiral recognition of various racemic compounds when used as the chiral packing material (CPM) for HPLC, which was commercialized in 1982 as the first chiral column based on an optically active polymer. This success encouraged us to develop further useful commercial chiral packing materials (CPMs) based on polysaccharides, cellulose, and amylose. By using these polysaccharide-based CPMs, particularly phenylcarbamate derivatives, nearly 90% of chiral compounds can be resolved not only analytically but also preparatively, and several chiral drugs have been produced using the CPMs. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1731,1739, 2009 [source] Enantiomeric separation of aminoglutethimide by capillary electrophoresis using native cyclodextrins in single and dual systemsJOURNAL OF SEPARATION SCIENCE, JSS, Issue 6-7 2003Adel M. Abushoffa Abstract Aminoglutethimide (AGT) is one of the few examples of chiral drugs that can be enantioseparated by capillary electrophoresis using any of the three native cyclodextrins: ,-, ,-, or ,-CD. A complete resolution of the enantiomers of this compound in cationic form could be achieved with each of the three CDs, using a pH 3 phosphoric acid-triethanolamine buffer. Affinity constants for AGT enantiomers with the three native CDs were determined, confirming that the highest selectivity was given by ,-CD while the strongest complexation was obtained with ,-CD. However, an opposite affinity pattern was observed with the latter. Selectivity was lower for AGT enantiomers in dual CD systems, compared to that obtained with a single selector at its optimal concentration, which confirms that dual systems are of more limited interest when the two selectors have a similar effect on the analyte mobility. These results are in good agreement with those predicted using recently developed mathematical models. [source] Three-Dimensional Pharmacology, a Subject Ranging from Ignorance to OverstatementsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2003Bertil Waldeck Nevertheless, chiral drugs have been developed and used as racemates, neglecting the fact that they comprise mixtures of two or more compounds which may have quite different pharmacological properties. A very limited access to pure enantiomers in the past has been responsible for this unsatisfactory state of affairs. During the last 20 years, significant achievements have made it possible to perform stereoselective synthesis and analysis. Today, novel chiral drugs are as a rule developed as single enantiomers. Yet, studies of old racaemic drugs are still designed, performed and published without mention of the fact that two or more compounds are involved. In recent years, a number of old racaemic drugs have been re-evaluated and re-introduced into the clinical area as the pure, active enantiomer (the eutomer). While in principle correct, the clinical benefit of this shift from a well established racaemate to a pure enantiomer often seems to be limited and sometimes exaggerated. Racaemic drugs with a deleterious enantiomer that does not contribute to the therapeutic effect (the distomer), may have been sorted out in the safety evaluation process. However, in the future any pharmacological study of racaemic drugs must include the pure enantiomers. This will generate new, valuable information on stereoselectivity in drug action and interaction. [source] Microseparation techniques for the study of the enantioselectivity of drug,plasma protein bindingBIOMEDICAL CHROMATOGRAPHY, Issue 3 2009Laura Escuder-Gilabert Abstract Stereoselectivity in protein binding can have a significant effect on the pharmacokinetic and pharmacodynamic properties of chiral drugs. The investigation of enantioselectivity of drugs in their binding with human plasma proteins and the identification of the molecular mechanisms involved in the stereodiscrimination by the proteins represent a great challenge for clinical pharmacology. In this review, the separation techniques used for enantioselective protein binding experiments are described and compared. An overview of studies on enantiomer,protein interactions, enantiomer,enantiomer interactions as well as chiral drug,drug interactions, including allosteric effects, is presented. The contribution of individual plasma proteins to the overall enantioselective binding and the animal species variability in drug,plasma protein binding stereoselectivity are reviewed. Copyright © 2008 John Wiley & Sons, Ltd. [source] Study on the enantiomeric ratio of the pharmaceutical substances alkannin and shikoninBIOMEDICAL CHROMATOGRAPHY, Issue 10 2004A. N. Assimopoulou Abstract The chiral pair alkannin and shikonin (A/S) are potent pharmaceutical substances with a wide spectrum of biological activity; their enantiomeric ratio does not in,uence the major biological activity studied hitherto. Nevertheless, in pharmaceutical development and approval of chiral drugs from the Health and Regulatory Authorities, full documentation of methods of analysis of enantiomeric drugs, is required in order to evaluate the enantiomeric purity of starting materials and ,nal products and to control the stability of enantiomers in pharmaceutical formulations under several experimental conditions. In the present study, the enantiomeric ratio of A/S was determined in several commercial samples of alkannin and shikonin and also the proportion of A/S derivatives in several Alkanna root samples, which are all used as active ingredients in pharmaceuticals. Light and air proved not to in,uence the enantiomeric ratio of A/S on a shikonin commercial sample, and temperature also did not alter the A/S ratio on shikonin and alkannin commercial samples. Microencapsulation of alkannin and shikonin commercial samples in ethylcellulose microspheres and also molecular inclusion of a shikonin commercial sample in , -hydroxypropyl-cyclodextrin, which are used as drug delivery systems, did not alter the A/S enantiomeric ratio. Copyright © 2004 John Wiley & Sons, Ltd. [source] Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodentsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003Nina Isoherranen Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer,enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P<0.05) more potent (ED50 values 11 mg kg,1, 46 mg kg,1 and 57 mg kg,1 at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED50 values 20 mg kg,1, 73 mg kg,1 and 81 mg kg,1 at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED50 values 16 mg kg,1, 20 mg kg,1 and 19 mg kg,1 respectively). In the hippocampal kindled rat a dose of 40 mg kg,1 of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg,1. Racemic PID also significantly increased the seizure threshold in this model. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer,enantiomer interaction. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer,enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture. British Journal of Pharmacology (2003) 138, 602,613. doi:10.1038/sj.bjp.0705076 [source] A consideration of the patentability of enantiomers in the pharmaceutical industry in the United States,CHIRALITY, Issue 6 2008Chris P. Miller Abstract During the last thirty years, concern over stereoselectivity of drug action has drawn a great deal of interest within the pharmaceutical field due to an improved understanding of the pharmacology and pharmacokinetics of enantiomers. Developing single enantiomers versus racemates or introducing a single enantiomer following the development of the racemic mixture appears to be the new trend. The intellectual property status of single enantiomers from racemates may be unclear. Drug discoverers and patent attorneys must examine the examples of the past to establish an appropriate pathway towards the development and intellectual property protection of chiral drugs. The review will focus on the patenting of an enantiomer in view of the prior art disclosure for the racemic mixture. Chirality, 2008. © 2008 Wiley-Liss, Inc. [source] Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery,Building chiral technology toolboxes,CHIRALITY, Issue 9 2007Oliver McConnell Abstract The application of Chiral Technology, or the (extensive) use of techniques or tools for the determination of absolute stereochemistry and the enantiomeric or chiral separation of racemic small molecule potential lead compounds, has been critical to successfully discovering and developing chiral drugs in the pharmaceutical industry. This has been due to the rapid increase over the past 10,15 years in potential drug candidates containing one or more asymmetric centers. Based on the experiences of one pharmaceutical company, a summary of the establishment of a Chiral Technology toolbox, including the implementation of known tools as well as the design, development, and implementation of new Chiral Technology tools, is provided. Chirality, 2007. © 2007 Wiley-Liss, Inc. [source] Sensitivity improvement of circular dichroism detection in HPLC by using a low-pass electronic noise filter: Application to the enantiomeric determination purity of a basic drugCHIRALITY, Issue 2 2007Marie Lorin Abstract The quality control of chiral drugs requires the determination of their enantiomeric purity. Nowadays, circular dichroism (CD) spectroscopy is gaining increasing importance in pharmaceutical analysis because of the commercially available CD detector in liquid chromatography. The separation of the two enantiomers of a basic drug (efaroxan) was achieved by high performance liquid chromatography using an amylose-derivated column with both UV and CD detections. A baseline-resolved separation (resolution: 5) was obtained after optimization of the mobile phase composition with hexane-ethanol-diethylamine (90:10:0.05; v/v/v). The use of a commercial low-pass electronic noise filter of the CD signal has improved the signal-to-noise ratio by a factor twelve and allowed the quantitation of each enantiomer in the 1.25,300 ,g ml,1 concentration range. The CD linear calibration curve, expressed in terms of stereoisomer height ratio versus concentration ratio, was plotted over the 0.4,6% range. A correlation coefficient greater than 0.999 was obtained by least-squares regression and the limit of detection for the distomer/eutomer ratio was estimated at 0.14%. Although the method validation showed good repeatability on the retention times (RSD < 0.9%), on the peak height ratios (RSD < 8.7%) of each enantiomer only up to 99.2% enantiomeric purity was achieved. Chirality, 2006. © 2006 Wiley-Liss, Inc. [source] Percutaneous permeation of enantiomers and racemates of chiral drugs and prediction of their flux ratios using thermal data: A pharmaceutical perspectiveCHIRALITY, Issue 5 2003Mohsen I. Afouna Abstract Albeit pharmacological, pharmacokinetic, and toxicological differences between enantiomeric pairs or between the pure enantiomers and racemate of chiral drugs are known to exist for decades, we are just beginning to realize that there are apparent differences between these species with respect to their percutaneous permeation as well. Such differences in permeation are likely to be enhanced when chiral drugs are formulated with chiral excipients, necessitating a careful assessment of the effect of formulation excipients on the permeation as well as the overall therapeutic outcomes. The in vitro transport data from the preclinical investigations, using laboratory animal models and/or in vitro cell culture systems, must be carefully validated in vivo as there are differences between these models and the human skin. Mathematical models such as MTMT that utilize the interdependence of certain physicochemical characteristics and percutaneous permeability have a predictive value in assessing the flux behavior of enantiomers and racemates. Chirality 15:456,465, 2003. © 2003 Wiley-Liss, Inc. [source] | |||||||||||||