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Chiral Switches: a Review Amit G Amit G. Nerkar et al. / Journal of Pharmacy Research 2011,4(4),1300-1303 Review Article Available online through ISSN: 0974-6943 http://jprsolutions.info Chiral switches: A Review Amit G. Nerkar*, Kedar S. Lade1, Nilam A. Gadhave2, Sanjay D. Sawant4 Asst. Professor (Pharmaceutical chemistry) Smt. Kashibai Navale College Of Pharmacy,Saswad Kondhwa Road, S. No 40/4, near Octroi post, Kondhawa (Bk),Pune 411048, Maharashtra, India. 1M.Pharm(Sem-III Student) Smt. Kashibai Navale College Of Pharmacy, Saswad Kondhwa Road, S. No 40/4, near Octroi post, Kondhawa (Bk), Pune 411048, Maharashtra, India. 3M.Pharm(Sem-III Student) Smt. Kashibai Navale College Of Pharmacy, Saswad Kondhwa Road, S. No 40/4, near Octroi post, Kondhawa (Bk), Pune 411048, Maharashtra, India. 4Professor & Principal Smt. Kashibai Navale College Of Pharmacy, Saswad Kondhwa Road, S. No 40/4, near Octroi post, Kondhawa (Bk), Pune 411048, Maharashtra, India. Received on: 05-12-2010; Revised on: 14-01-2011; Accepted on:09-03-2011 ABSTRACT Chiral drug are made up of molecule with the same chemical structure, but different three-dimensional arrangements. Modern manufacturing has enabled the development of products containing a single molecular arrangement. The development of these single enantiomers from chiral drugs is known as chiral switching. Enantiomers of the same drug can have different Pharmacodynamics and pharmacokinetic properties. This may translate into potential benefit, such as an improved safety margin, if one of the enantiomers has more favourable therapeutic and pharmacokinetic characteristics. However, some chiral switching has resulted in unpredicted toxicity and the withdrawal of the enantiomer from the marker or a half in its development. Drug companies are increasingly using chiral switching as a marketing strategy. But, before prescribers switch to single enantiomer drugs they should look for evidence from well-conducted clinical trials that show the chiral switch is cost-effective and improves the outcomes for patients rather than patents. Review describes the chiral switching of some compounds and their utility. Key words:Enantiomer, racemates, pharmacokinetics, adverse effects. INTRODUCTION Chirality is a fundamental characteristic of nature and pervades the living world. logues. By providing a description of the increasing potency of the molecule as the We have been under its constant influence throughout evolution as a result of the affinity of the enantiomer with a receptor increases, a series of compounds can be asymmetrical nature of the environment and, while the origin of this phenom- analysed and information provided for molecular design. There can potentially be enon is a matter of speculation, the evidence surrounds us all. Most proteins, for more than one eudismic ratio for a racemate if the compound has more than one example, are formed of L-amino acids while carbohydrates are composed of pharmacological effect. natural sugars, all D-isomers. Biological receptor systems comprise a complex structural organization of helices and sheets and display ‘handedness’. This results Advantages of The Use of Single Enantiomer Instead of The Racemic in a profound effect on drug–receptor interactions. Mixtures · The main advantage of working with single enantiomers is the absence The subject has fascinated scientists since the middle of the 19th century, when of the distomer which has its own pharmacokinetic and pharmacody- Louis Pasteur first demonstrated the stereoisomeric forms of tartaric acid. Follow- namic profile. ing earlier work by de la Provostaye, he undertook crystallographic studies on · Single enantiomer has a much better solubility in aqueous solutions than tartaric acid and its salts, and demonstrated the presence of hemihedral facets. In the racemate so the intravenous dosage form only contains the former. some instances, these were orientated to the left and in others to the right. By · Economical advantages of developing the single enantiomer instead of handpicking the crystals, he divided them into two groups and found that the the racemate. solutions rotated light in equal but opposite directions. Pasteur recognized that the cause of this phenomenon lay in the molecular structure, and by extending these When A Single Enantiomer Not Better Than A Racemic Mixture ideas he evolved the theory of the asymmetrical carbon atom. Optical isomerism · The first reason for administration of racemic drugs can be that there is enables the existence of two non-superimposable mirror images or enantiomers no difference between the individual enantiomers in their pharmacody (Greek enantios=opposite, meros=part) that share identical physicochemical namic and pharmacokinetic profiles. properties but differ in their rotation of plane-polarized light. Importantly, they A second reason can be that the effect is Stereospecific, i.e. the effect is 100% can also differ in pharmacological profile, owing to highly stereospecific interac- related to the eutomer and the distomer shows no side effects.When enantiomeric tions at the receptor interface. A mixture of two enantiomers is called a ‘race- inversion occurs in the body. mate’, a term popularized by Beilstein. A racemate is designated by the prefix (±) or rac-, or by the symbol RS or SR, and has no optical activity. The use of the term RACEMIC SWITCH ‘racemic mixture’ is to be discouraged as it is synonymously used as a synonym for Over the last ten to fifteen years drug chirality, particularly the use of single both ‘racemate’ and ‘racemic conglomerate’. enantiomers versus racemic mixtures become an area of considerable interest. As a result of advances in the chemical technologies associated with the synthesis, STEREOSPECIFIC BIOLOGICAL INTERACTIONS separation and analysis of the individual enantiomers present in a racemate, Interaction of a drug with a biological system produces a cascade of events that together with regulatory requirements the number of chiral drugs presented for ultimately leads to a point at which some physiological response can be measured. approval to regulatory authorities as single enantiomers rather than racemates has The initial interaction is highly stereospecific and a hypothesis to explain this was increased. In addition to new chemical entities a number of “old“racemates have proposed by Easson and Stedman in 1933. When comparing affinities, the been reevaluated as potential single enantiomer products with the possibility for enantiomer with the highest affinity is termed the ‘eutomer’ and that with the an improved therapeutic profile. These so-called Chiral Switches have resulted lowest affinity the ‘distomer’. The pharmacological activity of the two enanti- in a number of agents being commercially available as both single enantiomer and omers can therefore be compared by calculation of the ‘eudismic ratio’. Eudismic racemic mixtures at the same time. However, not all these re-evaluations have analysis provides a powerful tool for drug design, by optimizing a series of enanti- resulted in the expected therapeutic benefits and unpredicted adverse reactions omer pairs by the comparison of the eutomers and distomers in a series of ana- have resulted. The issues, both economic and therapeutic, associated with the Chiral Switch processes are addressed here. *Corresponding author. Dr. Amit G. Nerkar In recent years there has been considerable interest in the biological activity, both Asst. Professor (Pharmaceutical chemistry) pharmacological and toxicological, of the enantiomers of chiral drugs. This inter- Smt. Kashibai Navale College Of Pharmacy, est in drug stereochemistry has resulted from the considerable advances in the Saswad Kondhwa Road, S. No 40/4, synthesis analysis and separation of chiral molecules, together with an increased near Octroi post, Kondhawa (Bk), Pune 411048, appreciation of the potential significance of the differential biological properties Maharashtra, India. of the enantiomers of chiral drugs administered as racemates. As a result of these Journal of Pharmacy Research Vol.4.Issue 4. April 2011 1300-1303 Amit G. Nerkar et al. / Journal of Pharmacy Research 2011,4(4),1300-1303 advances in technology and the potential ben- efits of single enantiomer drugs, drug stereochem- istry became an issue for the pharmaceutical in- dustry and the regulatory authorities. A number of scientific meetings, involving academic, industrial and regulatory scientists, were held in the late 1980s – early 1990s with the specific objective of discussing the new technologies and the signifi- cance of chirality in pharmacology and therapeu- tics. Example of Drugs Which Undergo Racemic Switch A racemic or chiral switch may be defined as the development of a single enantiomer from a previously marketed racemate. Frequently the marketed single enantiomers have the same, or very similar, therapeutic indications as the origi- nally marketed racemate but this may not always be the situation and novel indications for”old“compounds have been reported. The chiral switch process has resulted in a number of agents being re-marketed as single enantiomer products (Fig.1) and a summary of these agents, together with their reported therapeutic advantages, is pre- sented in Table 1 Table 1. Racemate To Single Enantiomer: The Chiral Switch Fig.1. Marketed single enantiomers of agents which have undergone the chiral switch. Sr.no Drug Action/Indication Comment 1 Dexketoprofen Non-steroidal anti-inflammatory drug Inhibition of cyclooxygenase activity resides in the S-enantiomer, unlike
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