Putting chirality to work: the strategy of chiral switches

KEY POINTS * Chiral switches are chiral drugs that have already been claimed, approved and marketed as racemates or as mixtures of stereoisomers, but have since been redeveloped as single

enantiomers. The essential criterion of a chiral switch is a change in the status of chirality. There are still a significant proportion of racemic drugs among the recently approved new

molecular entities. * The patentability of single enantiomers in a chiral switch is an extreme case of a selection patent. The novelty of a single enantiomer is not negated by the prior-art

disclosure of its racemate. The strategy of enantiomeric pairs of patents of single enantiomers — E1 and E2 — in a chiral switch consists of two patents claiming simultaneously that E1 and

E2 are pharmacologically superior to the racemic drug E1,2. This strategy has been questioned. * According to the US FDA, single enantiomers in chiral switches are not new molecular

entities, and are therefore barred from five-years exclusivity. Such new products are treated as new derivatives of existing drugs or new formulations, on a case-by-case basis. * Despite the

regulatory acceptance of 'bridging strategies' from racemate to single enantiomer, only a few successful switches have emerged from this route. * Successful chiral switches emerge

from racemic drugs that have efficacy and/or safety that can be enhanced, leading to significantly superior single enantiomers that are patentable and compete effectively with cheaper

generic versions of the racemates. * Chiral switches are also eligible in cases in which the mechanisms of action of the single-enantiomer drugs involve achiral intermediates — for example,

esomeprazole magnesium — and/or racemization. * Paradoxically, a chiral switch can result in the increased use of the racemate, this being a feature of the failure of the chiral switch of

fenfluramine to dexfenfluramine and the 'fen–phen' fiasco. * The timing of chiral switches of blockbuster drugs is crucial. The new single enantiomer should be launched ideally

before the expiration of the patents that cover the racemate, with extended exclusivity and before the incursions of the respective generic drugs. 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. Access through your institution Buy or subscribe This is a preview of subscription

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THE HOMOCHIRAL WORLD Article 14 October 2022 DETECTION AND ANALYSIS OF CHIRAL MOLECULES AS DISEASE BIOMARKERS Article 20 March 2023 ENGINEERED ENZYMES FOR THE SYNTHESIS OF PHARMACEUTICALS

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_Optimising the Treatment of Mood and Anxiety Disorders_ 13–17 (Lundbeck, Copenhagen, 2002). Google Scholar  Download references 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 AUTHORS AND AFFILIATIONS * Division of Biomedical

Sciences, Imperial College Faculty of Medicine, Sir Alexander Fleming Building, London, SW7 2AZ, United Kingdom Israel Agranat & John Caldwell * Department of Organic Chemistry, The

Hebrew University of Jerusalem, Jerusalem, 91904, Israel Israel Agranat & Hava Caner Authors * Israel Agranat View author publications You can also search for this author inPubMed Google

Scholar * Hava Caner View author publications You can also search for this author inPubMed Google Scholar * John Caldwell View author publications You can also search for this author

inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Israel Agranat. RELATED LINKS RELATED LINKS DATABASES LOCUSLINK β2-adrenoceptor CB1 receptor CB2 receptor COX-1 COX-2 CYP2C19

TNF MEDSCAPE DRUGINFO albuterol amoxycillin bupivacaine citalopram hydrobromide dexmethylphenidate esomeprazole magnesium fexofenadine fluoxetine ibuprofen ketoprofen lansoprazole

levalbuterol levobupivacaine hydrochloride levofloxacin naproxen omeprazole pantoprazole phentermine rabeprazole thalidomide FURTHER INFORMATION Center for Drug Evaluation and Research

European Patent Office FDA Arthritis Drugs Advisory Committee Meetings International Conference on Harmonisation Medicines Control Agency US Food and Drug Administration US Patent and

Trademark Office 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 = _S_1; a centre of inversion, _i_ = _S_2; or a rotation–reflection axis, _S_2n). 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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Agranat, I., Caner, H. & Caldwell, J. Putting chirality to work:

the strategy of chiral switches. _Nat Rev Drug Discov_ 1, 753–768 (2002). https://doi.org/10.1038/nrd915 Download citation * Issue Date: 01 October 2002 * DOI: https://doi.org/10.1038/nrd915

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