Review Article

Putting chirality to work: the strategy of chiral switches

  • Nature Reviews Drug Discovery volume 1, pages 753768 (2002)
  • doi:10.1038/nrd915
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Abstract

Most of the new drugs reaching the market today are single enantiomers, rather than the racemic mixtures that dominated up to ten years ago. Many of the new single-enantiomer drugs were developed as such, but there are also important examples of new single-enantiomer drugs derived from 'chiral switches' of established racemates. Indeed, a well-timed chiral switch can offer enhanced therapy and further profitability as a 'line extension' of a major racemic drug with patents that are expiring.

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  1. β2-adrenoceptor

    • CB1 receptor

      • CB2 receptor

        • COX-1

          • COX-2

            • CYP2C19

              • TNF

                • albuterol

                  • amoxycillin

                    • bupivacaine

                      • citalopram hydrobromide

                        • dexmethylphenidate

                          • esomeprazole magnesium

                            • fexofenadine

                              • fluoxetine

                                • ibuprofen

                                  • ketoprofen

                                    • lansoprazole

                                      • levalbuterol

                                        • levobupivacaine hydrochloride

                                          • levofloxacin

                                            • naproxen

                                              • omeprazole

                                                • pantoprazole

                                                  • phentermine

                                                    • rabeprazole

                                                      • thalidomide

                                                        Acknowledgements

                                                        We thank S. K. Branch (Medicines Control Agency, London, UK), R. Perry (Gill, Jenning & Every, London, UK), S. P. Miller (Office of New Drug Products, FDA, Rockville, USA), P. Lindberg (AstraZeneca, Mulndal, Sweden), B. G. Larsson (AstraZeneca, Sodertalje, Sweden), J. Senn-Bilfinger (ALTANA Pharma, Konstanz, Germany), J. P. Leeds (Eli Lilly and Company, Indianapolis, USA) and J. W. Jaroszewski (Royal Danish School of Pharmacy, Copenhagen, Denmark) for enlightening discussions. I.A. became interested in chiral switches in 1996 as a Fellow of the Institute for Advanced Studies at The Hebrew University of Jerusalem, where he directed a research group on Chirality of Drugs and Chiral Recognition: New Challenges.

                                                        Author information

                                                        Affiliations

                                                        1. Division of Biomedical Sciences, Imperial College Faculty of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom.

                                                          • Israel Agranat
                                                          •  & John Caldwell
                                                        2. Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.

                                                          • Israel Agranat
                                                          •  & Hava Caner

                                                        Authors

                                                        1. Search for Israel Agranat in:

                                                        2. Search for Hava Caner in:

                                                        3. Search for John Caldwell in:

                                                        Corresponding author

                                                        Correspondence to Israel Agranat.

                                                        Glossary

                                                        CHIRALITY

                                                        The geometric property of a rigid object (or spatial arrangement of points or atoms) of being non-superimposable on its mirror image; such an object has no symmetry elements of the second kind (a mirror plane, σ = S1; a centre of inversion, i = S2; or a rotation–reflection axis, S2n). If an object is superposable on its mirror image, it is described as being achiral.

                                                        CONFORMATION

                                                        The spatial arrangement of the atoms affording distinction between stereoisomers, which can be interconverted by rotations about formally single bonds. A conformer is one of a set of stereoisomers, each of which is characterized by a conformation that corresponds to a distinct potential energy minimum.

                                                        CONFIGURATION

                                                        In the context of stereochemistry, the term is restricted to the arrangements of atoms of a molecular entity in space that distinguishes stereoisomers, the isomerism between which is not due to conformational differences. The absolute configuration is the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description — for example, R or S (for chiral centres) and M or P (for chiral axes).

                                                        RACEMATE

                                                        An equimolar mixture of a pair of enantiomers. It does not have optical activity. The chemical name or formula of a racemate is distinguished from those of the enantiomers by the prefix (±)- or rac- (or racem-), or by the symbols RS and SR.

                                                        PATENT

                                                        A grant by the state of exclusive rights for a limited time (in most jurisdictions 20 years from filing date) in respect of a new and useful invention. The patentable invention must be new, it must involve an inventive step and it must be capable of industrial application.

                                                        CHIRAL CENTRE

                                                        (Chirality centre). An atom that holds a set of ligands in a spatial arrangement, which is not superimposable on its mirror image. A chiral centre is, therefore, a generalized extension of the concept of the asymmetric carbon atom to central atoms of any element.

                                                        D,L

                                                        Configurational descriptors for carbohydrates and α-amino acids.

                                                        STEREOSELECTIVITY

                                                        The preferential formation in a chemical reaction of one stereoisomer over another. When the stereoisomers are enantiomers or diastereomers, the phenomenon is known as enantioselectivity or diastereoselectivity, respectively.

                                                        CLAIM

                                                        The part of a patent specification that defines the scope of protection.

                                                        EPIMERS

                                                        Diastereomers that have the opposite configuration at only one of two or more tetrahedral stereogenic centres that are present in the respective molecular entities.

                                                        PATENTABILITY

                                                        The basic conditions of patentability, which an application must meet if granted, are that the invention must be novel, contain an inventive step, be capable of industrial application and not be in one of several exluded fields.

                                                        NOVELTY

                                                        The essential condition for patentability that what is claimed is new.

                                                        INVENTIVE STEP

                                                        An invention is taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter that forms part of the state of the art, but not including matter from a patent application with an earlier priority date that is published later then the priority date of the invention (European Patent Convention, Section 3). The state of the art is the total information in the relevant field known to the hypothetical person skilled in the art.

                                                        INSUFFICIENCY

                                                        A ground of invalidity of a patent, if the description does not allow the skilled reader to work the invention.

                                                        CONSTITUTION

                                                        The description of the identity and connectivity (and corresponding bond multiplicities) of the atoms in a molecular entity (omitting any distinction that arises from their spatial arrangement).

                                                        PRIORITY DATE

                                                        The date on which an invention was first disclosed to a patent office in a patent application or in an earlier application from which it validly claims priority.

                                                        INTELLECTUAL PROPERTY LAW

                                                        An area of the law that concerns legal rights that are associated with creative effort or commercial reputation and goodwill.

                                                        OBVIOUS

                                                        Capable of being preformed by the average skilled person in possession of the prior art.

                                                        CHIRAL AXIS

                                                        (Chirality axis). An axis about which a set of ligands is held so that it results in a spatial arrangement that is not superimposable on its mirror image.

                                                        OPTICAL ACTIVITY

                                                        A sample of material that can rotate the plane of polarization of a beam of transmitted plane-polarized light is said to have optical activity (or to be optically active). This optical rotation is the classical distinguishing characteristic (which is sufficient but not necessary) of systems that contain unequal amounts of corresponding enantiomers. An enantiomer that causes rotation in a clockwise direction (when viewed in the direction that faces the incoming light beam) under specified conditions is called dextrorotatory and its chemical name or formula is designated by the prefix (+)-; one causing rotation in the opposite sense is laevorotatory and is designated by the prefix (−)-. Materials that have optical activity also have other chiroptic phenomena.

                                                        PRIOR ART

                                                        All public knowledge before the priority date that could be relevant to the novelty or unobviousness of an invention.