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Trends in the development of chiral drugs

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  • Drug chirality is now a major theme inthe design, discovery, development,launching and marketing of new drugs[14]. Stereochemistry is an essentialdimension in pharmacology [1]. In past decades the pharmacopoeiawas dominated by racemates, but sincethe emergence of new technologies inthe 1980s that allowed the preparationof pure enantiomers in significantquantities, the awareness and interestin the stereochemistry of drug actionhas increased [14].

    The advances in stereoselectivebioanalysis led to a new awareness of the importance of stereoselectivepharmacodynamics andpharmacokinetics, enabling thedifferentiation of the relativecontributions of enantiomers to overalldrug action. When one enantiomer isresponsible for the activity of interest,its paired enantiomer could be inactive,possess some activity of interest, be anantagonist of the active enantiomer orhave a separate activity that could bedesirable or undesirable [35].Considering these possibilities, thereappears to be major advantages inusing stereochemically pure drugs,such as a reduction of the totaladministered dose, enhancedtherapeutic window, reduction ofintersubject variability and a moreprecise estimation of doseresponserelationships [3,4]. These factors haveled to an increasing preference forsingle enantiomers in both industryand regulatory authorities. Regulatorycontrol of chiral drugs began in the US

    with the publication in 1992 of formalguidelines on the development of chiraldrugs in a document entitled PolicyStatement for the Development ofNew Stereoisomeric Drugs [6] and wasfollowed in the European Union (EU)in 1994 by Investigation of Chiral ActiveSubstances [7]. Applicants mustrecognize the occurrence of chirality in new drugs, attempt toseparate the stereoisomers, assess the contribution of the variousstereoisomers to the activity of interestand make a rational selection of thestereoisomeric form that is proposedfor marketing [4].

    Worldwide sales of chiral drugs insingle-enantiomer forms continue togrow. The market share of single-enantiomer dosage form drugsincreased annually from 27% (US $74.4 billion) in 1996, 29% (1997),30% (1998), 32% (1999), 34% (2000),38% (2001) to an estimate of 39%(US $151.9 billion) in 2002 [813].

    The top ten single enantiomerblockbuster drugs (>US $1 billion salesper year) are: Atorvastatin calcium[Pfizer;](cardiovascular); Simvastatin [Merck;] (cardiovascular);Pravastatin sodium [Bristol-MyersSquibb;](cardiovascular); Paroxetinehydrochloride [GlaxoSmithKline;] (CNS);Clopidogrel bisulfate [Sanofi-Synthelabo/Bristol-Myers Squibb;](hematology); Sertraline hydrochloride

    [Pfizer] (CNS); Fluticasone propionateand salmeterol xinafoate[GlaxoSmithKline] (respiratory);Esomeprazole magnesium [AstraZeneca;](gastrointestinal); Amoxicillin andpotassium clavulanate [GlaxoSmithKline](antibiotic); and Valsartan [Novartis;](cardiovascular) (Source: TechnologyCatalysts International) [13].

    The previously reported surveys ofchiral and achiral drugs have beenlimited in scope, each covering onlyshort periods and a single jurisdiction.Examples include an informal analysisof the 95 submissions of newchemical entities (NCEs) assessed bythe UK Medicines Control Agency[MCA; now Medicines and Healthcareproducts Regulatory Agency (MHRA)]in 19962000 [14], and an analysis ofthe new molecular entities (NMEs)approved by the FDA in 19982001( [15].

    In this article we evaluate andprovide an insight into thedevelopment of chiral and achiraldrugs and examine the impact of thison industrial drug development anddrug regulation worldwide.

    Methods of surveying approveddrugs according to chiralitycharacterTo survey the chirality character ofworldwide approved drugs, drugswere classified as being achiral, singleenantiomer or racemate. Racematesalso include diastereomeric mixtures

    DDT Vol. 9, No. 3 February 2004 updatefeature

    1359-6446/04/$ see front matter 2004 Elsevier Ltd. All rights reserved. PII: S1359-6446(03)02904-0

    Trends in the development of chiral drugsHava Caner, Efrat Groner and Liron Levy, Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel and Israel Agranat*, Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel and Division ofBiomedical Sciences, Faculty of Medicine, Imperial College, Sir Alexander Fleming Building, South Kensington, London SW72AZ, UK; *e-mail: [email protected]

  • for the purpose of this survey. Itshould be noted that racemates areconsidered to be chiral drugs. Thepresent analysis does not include newbiological entities (NBEs).

    The following two databases ofapproved drugs were surveyedaccording to the chirality character ofthe drugs: (i) To Market, To Market inAnnual Reports in Medicinal Chemistry,in the years 19832002 [16]. Thisdatabase lists all the new drugslaunched each year in worldwide

    markets; and (ii) new molecular entities(NMEs) also termed by the FDA as newchemical entities (NCEs), approved bythe FDA in the years 19912002( database lists all new drugsclassified as Chemical Type 1 (NME).NMEs are defined as active ingredientsthat have never been manufactured inthe US. The FDA classifies investigationalnew drug applications (INDs) and newdrug applications (NDAs) to assignreview priority on the basis of the

    Chemical Type (CHE) of the drug andpotential benefit (Box 1). According tothe FDA a chiral switch [4] is notclassified as a NME as it already containsa previously approved active moiety.

    Chiral switches are drugs that havealready been claimed, approved and/ormarketed as racemates or as mixturesof diastereomers, but have since beenredeveloped as single enantiomers[4,17]. The essential criterion of a chiralswitch is a change in the status ofchirality [4]. Thus, the chiral switches,esomeprazole magnesium (Nexium)(CHE 2), levobupivacaine hydrochloride[Chirocaine; AstraZeneca/Celltech(] (CHE 2),dexfenfluramine [Redux; Indevus/Wyeth ( and] (CHE 3;withdrawn), levofloxacin [Levaquin;Daiichi/Aventis/Ortho-McNeil(;; and] (CHE 3),levalbuterol [Xopenex; Sepracor(] (CHE 3),dexmethylphenidate [Focalin; Novartis/Cellgene (](CHE 3), levocetirizine hydrochloride[Xyzal, Xusal; Sepracor/UCB Farchim SA(] (CHE 3) and escitalopram oxalate

    update feature DDT Vol. 9, No. 3 February 2004


    Box 1. FDA classification of investigational new drugapplications (INDs) and new drug applications (NDAs)according to Chemical Type (CHE)

    Chemical Type (CHE)1 New Molecular Entity (NME): an active ingredient that has never been

    marketed in the US.2 New derivative: a chemical derived from an active ingredient already

    marketed (a parent drug).3 New formulation: a new dosage form or new formulation of an active

    ingredient already on the market.4 New combination: a drug that contains two or more compounds, the

    combination of which has not been marketed together in a product.5 Already marketed drug product, but a new manufacture: a product

    that duplicates another firms already marketed drug product (same activeingredient, formulation or combination).

    6 Already marketed drug product, but a new use: a new use for a drugproduct already marketed by a different firm.

    7 A drug that is already legally marketed without an approved NDA.

    Figure 1. (a) Distribution of worldwide-approved drugs according to chirality character in the period 19832002 (b) Distribution of FDAapproved drugs (NMEs) according to chirality character in the period 19912002. *Including diastereomeric mixtures.

    Drug Discovery Today







    Chiral centers

    Chiral centers


    Achirals42% Single




    (a) (b)

  • [Cipralex/Lexapro; H. Lundbeck/ForestLaboratories (] (CHE 3) arenot included among the NMEs (CHE 1).Most of the chiral switches appear inthe database of worldwide-approveddrugs [16].

    It should be noted that most (>90%) of the FDA-approved drugs in 19912002 were also included inthe database of worldwide approveddrugs, although not necessarily in thesame year.

    Figure 1a illustrates the totalworldwide distribution of 730 approveddrugs in 19832002 (including 382 in19912002) and the US distribution of304 FDA approved drugs (NMEs) in19912002 according to their chiralitycharacter. Table 1 and Figures 25describe the annual distributions ofworldwide approved drugs in theperiod 19832002 and of the FDA-approved drugs (NMEs) in the period19912002 and the corresponding fouryear (worldwide) and three year (FDA)range distributions.

    Distribution of worldwideapproved drugs, according tochirality character*19832002An overall look at the 20-year periodfrom 19832002 (Figure 1a) indicatesthat single-enantiomers surpassedachirals whereas racemates representedthe minority category at 23% ofworldwide approved drugs. Thepreponderance of single-enantiomerswas probably driven by the tide ofapproved single-enantiomer drugs thatoccurred since 1998. In the four-yearperiod from 19831986 (Figure 3),more racemic drugs (32%) wereapproved compared with singleenantiomer drugs and achiral drugsexceeded both categories of chiral

    drugs. However, even in this early timespan of the 1980s, singl

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