---· _ . . --- ___ ..
`
`-
`
`.
`
`.
`
`-·
`
`.
`
`- .
`
`Edited by Janos Fischer,
`C. Robin Ganellin and David P. Rotella
`
`($)WILEY-VCH
`
`Analogue-based
`Drug Discovery Ill
`
`International
`Union of Pure
`and Applied
`•
`Chemistry
`----~-------IUP-~:::a~ __ ___ __.
`
`•
`
`AstraZeneca Exhibit 2015
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 20
`
`

`
`Edited by jimos Fischer, C. Robin Ganef/in
`and David P. Rotella
`
`Analogue-based Drug Discovery Ill
`
`ffi
`
`WILEY(cid:173)
`VCH
`WILEY-VCH Verlag GmbH & Co. KGaA
`
`Page 2 of 20
`
`

`
`The Editors
`
`Prof Dr.Jimos Fischer
`Gedeon Richter Pic.
`Gyomriii ut 30
`1103 Budapest
`Hungary
`
`Prof Dr. C. Robin Cane/lin
`University College London
`Department of Chemistry
`20 Gordon Street
`London WCIH OAJ
`United Kingdom
`
`Prof Dr. David P. Rotella
`Montclair State University
`Department of Chemistry & Biochemistry
`Montclair, NJ 070-43
`USA
`
`Supported by the international Union of
`Pure and Applied Chemistry (!UPAC)
`Chemistry and Human Health Division
`PO Box 13757
`Research Triangle Park, NC 2770-3757
`USA
`
`All books published by Wiley-VCH are carefully
`produced. Nevertheless, authors, editors, and
`publisher do not warrant the information contained
`in these books, including this book, to be free of
`errors. Readers are advised to keep in mind that
`statements, data, illustrations, procedural details or
`other items may inadvertently be inaccurate.
`
`1
`
`Library of Congress Card No.: applied for
`
`British Library Cataloguing-in-Publication Data
`A catalogue record for this book is available from
`the British Library.
`
`Bibliographic information published by the Deutsche
`Nationalbibliothek
`The Deutsche Nationalbibliothek lists this
`publication in the Deutsche Nationalbibliografie;
`detailed bibliographic data are available on the
`Internet at http:f fdnb.d-nb.de.
`
`•<)2013 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12,
`69469 Weinheim, Germany
`
`All rights reserved (including those of translation into
`other languages). No part of this book may be
`reproduced in any form- by photoprinting,
`microfilm, or any other means- nor transmitted or
`translated into a machine language without written
`permission from the publishers. Registered names,
`trademarks, etc. used in this book, even when not
`specifically marked as such, are not to be considered
`unprotected by law.
`
`Print ISBN: 978-3-527-33073-7
`ePDF ISBN: 978-3-527-65111-5
`ePub ISBN: 978-3-527-65110-8
`mobi ISBN: 978-3-527-65109-2
`oBook ISBN: 978-3-527-65108-5
`
`Cover Design Grafik-Design Schulz, FufSgiinheim
`
`Typesetting Thomson Digital, Naida, India
`
`Printing and Binding Markono Print Media Pte Ltd,
`Singapore
`
`Printed on acid-free paper
`
`Page 3 of 20
`
`

`
`1
`Pioneer and Analogue Drugs
`janos Fischer, C. Robin Cane/lin, and David P. Rotella
`
`A pioneer dn1g ("first in class") represents a breakthrough invention that affords a
`marketed drug where no structurally andjor pharmacologically similar drug was
`known before its introduction. The majority of drugs, however, are analogLie drugs,
`which have structural andjor pharmacological similarities to a pioneer drug or, as
`in some cases, to other analogue drugs.
`The aim of this chapter is to discuss these two drug types [1 ].
`The term "pioneer drug" is not used very often, because only a small fraction of
`drugs belongs to this type and in many cases the pioneer drugs lose their impor(cid:173)
`tance when similar but better drugs are discovered. A pioneer drug and its ana(cid:173)
`logues form a drug class in which subsequent optimization may be observed.
`Analogue drugs typically offer benefits such as improved efficacy andjor side
`effect profiles or dose frequency than a pioneer drug to be successful on the
`market.
`The discovery of both pioneer and analogue drugs needs some serendipity. A pio(cid:173)
`neer drug must clinically validate the safety and efficacy of a new molecular target
`and mechanism of action based on a novel chemical structure. In the case of an
`analogue drug, it is helpful that a pioneer or an analogue exists; nevertheless, some
`serendipity is needed to discover a new and better drug analogue, because there are
`no general guidelines on how such molecules can be identified preclinically. The
`analogue approach is very fruitful in new drug research, because there is a higher
`probability of finding a better drug than to discover a pioneer one. A significant risk
`with this approach is based on the potential for one of the many competitors in the
`drug discovery area to succeed prior to others.
`The similarity between two drugs cannot be simply defined. Even a minor modi(cid:173)
`fication of a drug structure can completely modify the properties of a molecule.
`Levodopa (1) and methyldopa (2) are applied in different therapeutic fields; how(cid:173)
`ever, their structures differ only in a methyl group. Both molecules have the same
`stereochemistry as derivatives of L-tyrosine. Levodopa (2] is used for the treatment
`of Parkinson's disease as a dopamine precursor, whereas methyldopa (3] was an
`important antihypertensive agent before safer and more efficacious molecules
`(e.g., ACE inhibitors) appeared on the market.
`
`A11alogue-based Drug Discove1y I II, First Edition. Edited by Janos Fischer, C. Robin Ganellin, and
`David P. Rolelb.
`'' 2013 Wiley-VCH Verlag Gmbll & Co. J<Gai\. Published 2013 by Wiley-VCII Verlag GmbH & Co. l<GaA.
`
`Page 4 of 20
`
`

`
`417 Pioneer and Analogue Drugs
`
`Methyldopa (first synthesized at Merck Sharp & Dohme) has a dual mechanism
`of action: it is a competitive inhibitor of the enzyme DOPA decarboxylase and its
`metabolite acts as an a-adrenergic agonist.
`
`0
`
`HOdOH
`I ~ NH
`
`2
`
`HO
`
`levodopa
`1
`
`0
`
`HO~OH
`~H2
`
`HO)l)
`
`methyldopa
`2
`Levodopa and methyldopa are not analogues from the viewpoint of medicinal
`chemistry. Both are pioneer drugs in their respective therapeutic fields and can be
`considered as stand-alone drugs, because they have no successful analogues.
`There are several examples, and it is a usual case that a minor modification of a
`drug molecule affords a much more active drug in the same therapeutic field. The
`pioneer drug chlorothiazide (3) and its analogue hydrochlorothiazide (4) from
`Merck Sharp & Dohme differ only by two hydrogen atoms; however, the diuretic
`effect of hydrochlorothiazide [4] is 10 times higher than that of the original drug.
`The pioneer drug chlorothiazide is rarely used, but its analogue, hydrochlorothia(cid:173)
`zide, is an important first-line component in current antihypertensive therapy as a
`single agent and in combination with other compounds.
`0
`0
`'::::-~
`I -....::::
`NH
`~ NJ
`
`NH2-so2:ccs,
`
`Cl
`
`chlorothiazide
`3
`
`0
`0
`'::::-~
`NH2-S02:CCS ,
`I -....::::
`NH
`~ N)
`
`Cl
`
`H
`hydrochlorothiazide
`4
`Chlorothiazide and hydrochlorothiazide are direct analogues, which term empha(cid:173)
`sizes their close relationship.
`The terms "pioneer drugs" and "analogue drugs" will be discussed in the follow(cid:173)
`ing sections.
`
`Page 5 of 20
`
`

`
`1. 1 Monotarget Drugs Is
`
`1.1
`Monotarget Drugs
`
`1.1.1
`H 2 Receptor Histamine Antagonists
`
`Before the launch of cimetidine (1976), only short-acting neutralization of gastric
`acid was possible by administration of various antacids (e.g., sodium bicarbonate,
`magnesium hydroxide, aluminum hydroxide, etc.) that did not affect gastric acid
`secretion. Cimetidine [5], the first successful H2 receptor histamine antagonist, a
`pioneer drug for the treatment of gastric hyperacidity and peptic ulcer disease, was
`discovered by researchers at Smith, Kline & French. The inhibition ofhistamine(cid:173)
`stimulated gastric acid secretion was first studied in rats. Burimamide (5) was the
`first lead compound, a prototype drug, that also served as a proof of concept for
`inhibition of acid secretion in human subjects when administered intravenously,
`but its oral activity was insufficient. Its analogue, metiamide (6), was orally active,
`but its clinical studies had to be discontinued because of a low incidence of granu(cid:173)
`locytopenia. Replacing the thiourea moiety in metiamide with a cyanoguanidino
`moiety afforded cimetidine (7). Its use provided clinical proof for inhibition of gas(cid:173)
`tric acid secretion and ulcer healing and was a great commercial and clinical suc(cid:173)
`cess in the treatment of peptic ulcer disease.
`
`burimamide
`5
`
`metiamide
`6
`
`cimetidine
`7
`
`Page 6 of 20
`
`

`
`61 7 Pioneer and Analogue Drugs
`
`Although cimetidine was very effective for the treatment of peptic ulcer disease
`and related problems of acid hypersecretion, there were some side effects associ(cid:173)
`ated with its use, albeit at a very low level. A low incidence of gynecomastia in men
`can occur at high doses of cimetidine due to its antiandrogen effect. Cimetidine
`also inhibits cytochrome P450, an important drug metabolizing enzyme. It is there(cid:173)
`fore advisable to avoid coadministration of cimetidine with certain drugs such as
`propranolol, warfarin, diazepam, and theophylline.
`Cimetidine led to the initiation of analogue-based drug research affording more
`potent analogue drugs such as ranitidine (8) and famotidine (9) that lack the above
`side effects of cimetidine.
`
`famotidine
`9
`
`Ranitidine [6] also has a pioneer character, because ranitidine is the first H 2
`receptor histamine antagonist that has no antiandrogen adverse effect and does not
`inhibit the cytochrome CYP450 enzymes. Famotidine is the most potent member
`of this drug class, which has been discussed in Volume I of this series [7].
`Summary:
`
`Pioneer H 2 receptor histamine antagonist: cimetidine.
`First H 2 receptor histamine antagonist with no antiandrogen adverse effects and
`without inhibition of P450 enzymes: ranitidine.
`
`1.1.2
`ACE Inhibitors
`
`A natural product, the nonapeptide teprotide (10), was the pioneer drug for angio(cid:173)
`tensin-converting enzyme (ACE) inhibitors. Teprotide [8] was used as an active anti(cid:173)
`hypertensive drug in patients with essential hypertension. It could only be
`administered parenterally, which is a great drawback for chronic use of a drug. A
`breakthrough occurred with the approval of the first orally active ACE inhibitor cap(cid:173)
`topril (11) in 1980 by Squibb. Captopril [9] has a short onset time (0.5-1 h), and its
`duration of action is also relatively short (6-12 h); as a result, two to three daily
`doses are necessary. Captopril can be regarded as a pharmacological analogue of
`teprotide, but it is also the pioneer orally active ACE inhibitor. Captopril's discovery
`
`Page 7 of 20
`
`

`
`7. 7 Monotarget Drugs 17
`
`initiated intensive research by several other drug companies to discover longer act(cid:173)
`ing ACE inhibitors. Enalapril (12) was introduced by Merck in 1984. Enalapril [10]
`can be regarded as the first long-acting oral ACE inhibitor. The long-acting ACE
`inhibitors are once-daily antihypertensive drugs. There are several long-acting ACE
`inhibitors, whose differences have been discussed in the first volume of this book
`series [11].
`
`pyro-Giu - Trp - Pro - Arg - Pro- Gin - lie - Pro- Pro -OH
`
`teprotide
`10
`
`HsJyQ
`
`0
`
`COOH
`
`captopril
`11
`
`EtOOC
`
`CH, Nq
`
`~lr COOH
`
`enalapril
`12
`
`Summary:
`
`Pioneer ACE inhibitor drug: teprotide.
`First orally active ACE inhibitor drug: captopril.
`First orally long-acting ACE inhibitor drug: enalapril.
`
`1.1.3
`DPP IV Inhibitors
`
`Sitagliptin (13) [12], a pioneer dipeptidyl peptidase IV (DPP IV) inhibitor, was
`launched in 2006 by Merck for the treatment of type 2 diabetes. The medicinal
`chemistry team began its research in 1999 when some DPP IV inhibitor molecules
`were known as substrate-based analogues. The lead molecule derived from this
`research was vildagliptin (14) [13]; discovered at Novartis in 1998, it was the second
`compound to be introduced to the market.
`
`sitagliptin
`13
`
`Page 8 of 20
`
`

`
`sl 7 Pioneer and Analogue Drugs
`
`vildagliptin
`14
`
`The pioneer drug sitagliptin is a commercial success with 2010 sales greater than
`USD 3 billion. Vildagliptin was the first successful discovery in this drug class, but
`its development time was longer and it was introduced in 2007, after sitagliptin.
`Vildagliptin is only moderately selective over DPP-8 and DPP-9 compared to sita(cid:173)
`gliptin that is a highly selective DPP IV inhibitor. Based on long-term safety stud(cid:173)
`ies, these selectivity differences do not influence the toxicity of vildagliptin.
`Sitagliptin and vildagliptin show similar clinical efficacies. Vildagliptin has a short
`halflife (3 h) and its dosing regimen is twice a day, whereas sitagliptin has a long
`half-life (12 h) and once-daily dosing is used. DPP IV inhibitors are typical early(cid:173)
`phase analogues that result from a highly competitive industry, and not the first
`candidate (vildagliptin) but a follow-on drug (sitagliptin) became the pioneer drug
`on the market ("first-in-class drug"). Further DPP IV inhibitors are available (alog(cid:173)
`liptin, saxagliptin, and linagliptin) and the individual compounds differ signifi(cid:173)
`cantly in their mode of metabolism and excretion and these differences help the
`treatment of patients with type 2 diabetes in an individual way [14] (see Chapter 5
`ofVolume II of this book series).
`Summary:
`
`Pioneer DPP IV inhibitor drug: sitagliptin (long-acting inhibitor).
`First DPP IV inhibitor analogue drug: vildagliptin (short-acting inhibitor).
`
`1.1.4
`Univalent Direct Thrombin Inhibitors
`
`Thrombin is a serine protease enzyme whose inhibition plays an important role in
`the mechanism of several anticoagulants. Univalent direct thrombin inhibitors bind
`only to the active site of the enzyme, whereas bivalent direct thrombin inhibitors
`(e.g., hirudin and bivalirudi~) block thro~bi~ at ~~th the active site and exosite 1.
`The pioneer univalent direct t~~ro~bm mlnb1tor is argatroban monohydrate
`(15) [15] that was launched by Danchi Pharmaceutical and Mitsubishi Pharma in
`1990. Argatroban was approved by the FDA for prophylactic anticoagulation in the
`treatment of thrombosis in patient~ wit~ h:p.arin-induced thrombocytopenia. Arga(cid:173)
`troban is a rather selective revers~ble m~n~Itor for human thrombin. Despite its
`low molecular weight, argatr~~an IS ad~mmstered parenterally due to the presence
`of the highly basic guamdme mOiety that prevents absorption from the
`
`Page 9 of 20
`
`

`
`1. 1 Monotarget Drugs 19
`
`gastrointestinal tract. This characteristic limits the clinical use of the compound.
`The first oral direct thrombin inhibitor was ximelagatran (17) [16], which was intro(cid:173)
`duced in 2004 by AstraZeneca. Ximelagatran is a double prod rug derivative of mel(cid:173)
`agatran (16) with a bioavailability of about 20%, a measurable improvement
`compared to melagatran with oral bioavailability of 5.8%. Ximelagatran was with(cid:173)
`drawn from the market in 2006 because of unacceptable hepatic side effects (ala(cid:173)
`nine aminotransferase increased threefold and bilirubin level increased twofold
`above the normal upper limit) [17]. In this drug class, dabigatran etexilate (18) [18]
`was discovered by Boehringer Ingelheim as a new direct thrombin inhibitor with(cid:173)
`out adverse liver effects [19] (see Chapter 10)
`
`us~/~JOH
`L!H H)t)
`•,
`
`2
`
`H
`
`argatroban monohydrate
`15
`
`melagatran
`16
`
`ximelagatran
`17
`
`N~
`
`0
`
`0
`
`1~r-1~N~O~
`u
`~0 0
`N NJ l ) ~N
`I
`
`H
`
`CH3-SOpH
`
`dabigatran etexilate mesylate
`18
`
`Page 10 of 20
`
`

`
`10 17 Pioneer and Analogue Drugs
`
`Summary:
`
`Pioneer univalent direct thrombin inhibitor drug: argatroban.
`First orally active univalent thrombin inhibitor: ximelagatran.
`First orally active univalent thrombin inhibitor without adverse liver affects: dabi(cid:173)
`gatran etexilate.
`
`1.2
`Dual-Acting Drugs
`
`1.2.1
`Monotarget Drugs from Dual-Acting Drugs
`
`1.2.1.1 Optimization of Beta-Adrenergic Receptor Blockers
`James W. Black and coworkers at ICI invented propranolol as a product of analogue(cid:173)
`based drug discovery (ABDD) using their prototype drug, pronethalol (19), as a lead
`compound. Pronethalol [20] was an active drug for the treatment of angina pectoris
`in humans, but its development was discontinued because it proved to be carcino(cid:173)
`genic in mice in long-term toxicology studies. Continuation of the analogue-based
`drug discovery afforded propranolol (20), where an oxymethylene link was inserted
`between the 1-napthyl group and the secondary alcohol moiety of pronethalol. Pro(cid:173)
`pranolol [21] was more potent than pronethalol. Propranolol became the pioneer
`nonselective f3-adrenergic receptor antagonist, a true antagonist without partial ago(cid:173)
`nist properties (intrinsic sympathomimetic activity). It was a breakthrough discovery
`for the treatment of arrhythmias, angina pectoris, and hypertension.
`
`pronethalol
`19
`
`c6 OH H
`o~NJ__
`
`propranolol
`20
`
`atenolol
`21
`
`Page 11 of 20
`
`

`
`7.2 Dual-Acting Drugs Ill
`The pioneer drug propranolol has equal antagonist affinity for f) 1 and [32 adrener(cid:173)
`gic receptors; however, f) 1 receptors are located only in the heart and the non(cid:173)
`selective propranolol also blocks [32 receptors in bronchial smooth muscle.
`Therefore, propranolol is not used in patients with bronchial asthma. Several ana(cid:173)
`logues have been tested in a battery of in vivo pharmacological tests resulting in the
`discovery of atenolol (21) [22]. A guinea pig bronchospasm test served for investiga(cid:173)
`tion and demonstration of [3 1 selectivity. Atenolol had no intrinsic sympatho(cid:173)
`mimetic effect (partial agonism), similar to propranolol (see Chapter 8 of Volume I
`(Part II) of this book series).
`Summary:
`
`Pioneer dual-acting ([} 1 and [}2 ) beta-adrenergic receptor antagonist: propranolol.
`First [) 1 selective antagonist drug without intrinsic sympathomimetic activity.
`atenolol.
`
`1.2.2
`Dual-Acting Drugs from Monotarget Drugs
`
`1.2.2. 1 Dual-Acting Opioid Drugs
`Most ligands designed from the morphine template are mu (~t) opioid receptor
`(MOP) agonists. A simplified version of the morphine skeleton afforded tramadol
`that is marketed in its racemic form. The (+)-isomer is a weak MOP agonist,
`whereas the (-)-isomer inhibits neurotransmitter reuptake. Tramadol (22) [23] was
`discovered by Griinenthal and was introduced in 1977 for the treatment of moder(cid:173)
`ate to severe pain.
`
`o......._
`tramadol
`22
`
`~S::
`
`OH
`
`tapentadol
`23
`
`Page 12 of 20
`
`

`
`1217 Pioneer and Analogue Drugs
`
`Griinenthal continued analogue-based drug research using tramadol as a
`starting compound, and out of several analogues, tapentadol (23) [24] was
`selected and developed. It was introduced in 2009 to the market as a new opioid
`analgesic drug with dual activity: a MOP agonist and an inhibitor of nor(cid:173)
`epinephrine reuptake. Tramadol is thousands of times less potent than mor(cid:173)
`phine on the mu opioid receptor, whereas tapentadol's analgesic activity is
`comparable to that of oxycodone with reduced constipation and respiratory
`depression (see Chapter 12).
`
`Summary:
`
`Pioneer dual-acting (MOP agonist and norepinephrine reuptake inhibitor) opioid
`drug racemate: tramadol.
`First dual-acting (MOP agonist and norepinephrine reuptake inhibitor) opioid
`drug in a single molecule: tapentadol.
`
`1.3
`Multitarget Drugs
`
`1.3.1
`Multitarget Drug Analogue to Eliminate a Side Effect
`
`1.3.1.1 Clozapine and Olanzapine
`Clozapine (24) [25] is the pioneer drug in the class of atypical antipsychotic agents.
`It was a serendipitous discovery by researchers at Wander in Switzerland in 1960
`from the structural analogue antidepressant amoxapine (25). Its discovery was
`unexpected from the structurally very close analogue and therapeutically it had a
`great advantage over the typical antipsychotic drugs such as chlorpromazine and
`haloperidol because clozapine produced no extrapyramidal side effects (EPS). Clo(cid:173)
`zapine causes agranulocytosis in about 1% of the patients, and this side effect lim(cid:173)
`ited its application. Analogue-based drug design afforded quetiapine (26) [26], a
`clozapine analogue without this side effect. It was discovered at ICI in 1986 and it
`became one of the main products of AstraZeneca. Instead of the dibenzodiazepine
`nucleus of clozapine, the analogue quetiapine has a dibenzothiazepine scaffold.
`Both clozapine and quetiapine have affinity for a number of receptors. The antipsy(cid:173)
`chotic activity is believed to be associated primarily by virtue of affinity for Dz and
`5-HTzA receptors. Chapter 3 discusses metabolic aspects that may contribute to the
`distinct adverse event profiles of these two drugs (see the chapter of Volume I on
`clozapine analogues).
`
`Summary:
`
`Pioneer atypical antipsychotic drug: clozapine.
`First atypical clozapine-like antipsychotic drug without the side effect of agranu(cid:173)
`locytosis: quetiapine.
`
`Page 13 of 20
`
`

`
`1.3 Multitarget Drugs In
`
`clozapine
`24
`
`H
`
`(N NJ
`d=:trCI
`
`amoxapine
`25
`
`quetiapine
`26
`
`1.3.2
`Selective Drug Analogue from a Pioneer Multitarget Drug
`
`1.3.2.1 Selective Serotonin Reuptake Inhibitors
`From a retrospective viewpoint, imipramine (27) was the pioneer antidepressant
`drug with a multitarget receptor profile, where serotonin and norepinephrine
`reuptake inhibition played an important role, but no in vitro activities were known
`at the time of its serendipitous discovery. Researchers at Geigy first synthesized the
`molecule in 1948. It was an analogue of the antipsychotic chlorpromazine (28), but
`the Swiss psychiatrist Roland Kuhn [27] found imipramine to be an effective anti(cid:173)
`depressant drug. It was launched by Geigy in 1959.
`
`Page 14 of 20
`
`

`
`1417 Pioneer and Analogue Drugs
`
`imipramine
`antidepressant
`27
`
`I !"'
`o:N:crCI
`
`s
`chlorpromazine
`antipsychotic
`28
`
`Imipramine and the analogue tricyclic antidepressants inhibit the reuptake of
`serotonin and norepinephrine but they also exhibit a variety of side effects. The
`anticholinergic side effects include dry mouth, blurred vision, and sinus tachycar(cid:173)
`dia. The histamine H 1 receptor antagonist activity likely contributes to the sedative
`effects associated with the compound.
`
`_..,:;
`N
`
`Br
`
`zimelidine
`29
`
`Arvid Carlsson initiated research on selective serotonin reuptake inhibitors
`(SSRis) in order to get new antidepressants with less side effects. The first SSRI
`was zimelidine (29) [28]. It was launched by Astra in 1982, but it had to be with(cid:173)
`drawn shortly afterward because of serious peripheral nerve side effects. Further
`research was continued at several pharmaceutical companies. The first successful
`SSRis were fluoxetine (30) [29] (Lilly, 1988) and citalopram (31) [30] (Lundbeck,
`1989). The antihistamine diphenhydramine (32) served as a lead compound for
`fluoxetine, whereas talopram (33) was the lead structure for citalopram. The
`
`Page 15 of 20
`
`

`
`discovery of citalopram and its refinement to escitalopram is discussed in
`Chapter 11.
`
`7.3 Multitarget Drugs 115
`
`rl
`~
`~'CH3
`('Yo
`FC~
`
`3
`
`fluoxetine
`30
`
`NC
`
`F
`
`citalopram
`31
`
`diphenhydramine
`(lead for fluoxetine)
`32
`
`talopram
`(lead for citalopram)
`33
`
`Summary:
`
`Pioneer multitarget nonselective serotonin/norepinephrine reuptake inhibitor
`antidepressant drug: imipramine.
`First (but unsuccessful) selective serotonin reuptake inhibitor: zimelidine.
`First selective serotonin reuptake inhibitors: fluoxetine and citalopram.
`
`Page 16 of 20
`
`

`
`16
`
`1 1 Pioneer and Analogue Drugs
`~---~
`
`Figure 1.1 Pioneer drugs and drug ana logues have overl apping properties.
`
`1.4
`summary
`
`Pion eer drugs open up new therapeutic treatments. They are al so called "first-in(cid:173)
`class" drugs.
`Analogue-based drug di scovery is a very important part of medicinal ch emi sb·y,
`because the analogues frequently are intended to optimize drug therapy. There is a
`continuous development in a drug class and in several cases the pioneer drugs disap(cid:173)
`pear from the market and analogue drugs achieve a dominant role. It is the main rea(cid:173)
`son why so many successful drugs are among the analogue drugs. The above exa mples
`focused on some cases where these drugs have a unique character in a drug class.
`For early-phase analogues, it is possible that a pion eer drug derives from the ana(cid:173)
`logue-based drug discovery for different reasons; for example, a more convenient
`lead compound or a more successful optimization can strongly influ ence which
`drug wi ll be introduced to the market as a pioneer drug.
`There are several exa mples where a new prototype drug candidate was di scontin·
`ued at th e late phase of drug research and then an ana logue wa s introduced to th e
`market as a successful pioneer drug.
`The properties of pioneer and analogue drugs overlap (Figure 1.1). The drug ana(cid:173)
`logues preserve some properties of the pioneer dru g and they have to achieve so me
`new and better properties in order to be successful on the market.
`
`Acknowledgments
`
`We thank Klaus Peter B0ges0, 1-Telrnut Buschmann, Jens-Uwe Peters, and Henning
`Priepke for carefully reading and reviewing the manuscript.
`
`References
`
`1 Fischer, J. (2011) Pioneer and analogue
`drLigs. 43rd I UPAC World Chemistry
`Congress, August 3, 2011, San juan,
`Puerto Rico, Abstract No. 848.
`
`2 Carlson , A. (1971) R~cenL Advances in
`Parkinson's Ois~ase (eels F. H. McDowett
`and C. H. Markham) , Davis, Philadelphia,
`PA, pp. 1- 10.
`
`Page 17 of 20
`
`

`
`References 117
`
`3 Oates, ).A., Gillespie, S., Udenfi:iend, S.,
`and Sjoerdsma , A. (1960) Decarboxylase
`inhibition and blood pressure reduction of
`alpha methy l-3,4-dihydroxy-LJL(cid:173)
`phenylalanine. Science, 131, 1890-1891.
`4 DeSteve ns, G. , We rner, L.H. ,
`Holarnandri s, A., and Ricca, S. , Jr.
`(1958) Dihydrobenzothiazine diox ides
`with potent diuretic effect. fixpaientia,
`14, 463.
`5 Ganellin, C.R. (1982) Cimct"idine, in
`Chr011icb of Drug Discovery, vol. 1 (eels J. S.
`Nindra and D. Led nicer) , john Wiley and
`Sons, Inc. , New York, pp. 1- 38.
`6 Pearce, P. and Funder, J.W. (1980)
`Histamine l-Iz-receptor antagonist:
`radioreceptor assay for antiandrogenic
`side effects. C/.i.n. fixp. f>harmawl. t>ltysi.ol.,
`7, 442.
`7 Ganellin, C.R. (2006) Development of
`an tiulcer l-Iz-receptor histamine
`antagon ists, in Analogue-Based Drug
`Discovery (eds ). Fischer and C.R.
`Ganellin) , Wi ley-VCH Verlag GmbH,
`Weinheim, pp. 71- 80.
`8 Bakh le, Y.S. (1972) Inhibition of
`converting enzyme by venom peptides, in
`1-/ypertension (eds J. Genest ;mel E. Koiw),
`Springer, Berli n, pp. 541- 547.
`9 Ondetti , M.A., Rubin, B., and Cushman ,
`D. W. (1977) Design of specific inhibitors
`of ang iotensin-converting enzyme: new
`class of orally active antihypertensive
`agents. Science, 196, 441-444.
`10 Patchett, A.A., Harris, E. , Tristram , E.W.,
`Wyvratt, M.J., Wu, MT, Taub, D.,
`Peterson, E.R., lkcler, T J., Te n Broeke, J.,
`Payne, G., Ondeyka, D.L. , Thorsetl, E. D.,
`Greenlee, W.j., Loh r, N.S., HofTsornmer,
`R.D. , joshua, H. , Ruyle,)., Rothrock, W.,
`Aster, S.D., Maycock, A. L., Robinson,
`F.M. , Hirschmann, R., Sweet, C.S ., Ulm,
`E. H., Gross, D.M ., Vassil , C. , and Stone,
`C. A. (1980) A new class of angiotensin(cid:173)
`converting enzyme inhibitors. Nat.f!re ,
`288, 280-283.
`11 Alfo ldi , S. and Fische r,). (2006)
`Optimizing antih ypertensive therapy by
`ang iotensin converting enzyme
`inhibitors, in Analog1.1e-Based Drug
`Discove1y (eds J. Fi scher and C. R.
`Ganellin) , Wiley-VC I-1 Verlag GmbH ,
`Weinheim, pp. 169- 179.
`
`12 Biftu, T, Scapin , G., Singh , S., Feng, D.,
`Becke r, J.W. , Eiermann, G., He, H., Lyons,
`K., Patel, S. , Petrvov, A., Sinha- Roy, R.,
`Zhang, B., Wu, )., Zhang, X., Doss, G.A. ,
`Thornberry, N.A ., and Weber, A. E. (2007)
`Rational design of a novel, potent and
`orall y bioavailable cyclohexylarnine DPP-4
`inhibitor by application of molecular
`modeling and X-ray crystallography of
`sitagli ptin. Bioorg. Med. Chem. Lc:tt. , 17,
`3384--3387.
`13 Villhauer, E. B., Brinkmann, J. A., Naderi,
`G.B., Burkey, B.r:., Dunning, B. E., Prasad ,
`K., Mangold , B.L., Russell, M.E., and
`Hughes, T.E. (2003) 1-[[(3-Hydroxy-1-
`ada man tyl)a 111 i no ]acetyl]-2-cyano-( S)(cid:173)
`pyrrolidine: a potent, selective, and ora ll y
`bioavailable dipeptidyl peptidase IV
`inhibitor with antihyperglycemic
`properties.). Mc:d. Chc:m., 46, 2774--2789.
`14 Peters, J.- U. and Mattei, P. (2010)
`Dipeptidyl peptidase IV inh ibitors for the
`treatment of type 2 diabetes, in Analogue(cid:173)
`Based Drug Discovay II (eels J. Fischer and
`C.R. Ganellin), Wiley-VCI-1 Verlag Gmb.l-1,
`Weinheim, pp. 109- 134.
`15 Jeske, W., Walenga, j.M ., Lewis, B. E., and
`Fa reed, J. (1999) Pharmacology of
`argalroban. fixpc:rt. Opin. lnvc:st. Drugs, 8
`(5), 625- 654.
`16 Gustafsson, D. and Elg, M. (2003) The
`pharmacodynamics and pharmacokinetics
`of the oral direct thrombin inh ibi tor
`ximelagatran and its active me tabolite
`melagatran: a min i-review. Throm.b. Res.,
`109 (Suppl. 1.) , S9-S15.
`17 Lee, W.M., Laney, D. , Olsson, R., Lewis, J.
`H. , Keisu, M ., Auclert, L. , and Shet, S.
`(2005) Hepatic findings in long-term
`clin ical trials of xirnelagatran. Drug Sa{.
`28 (4), 351- 370.
`18 Hauel, N. H., Nar, H. , Priepke, H., Ries,
`U., Stassen, j.M., and Wienen, W. (2002)
`Structure-based design of novel potent
`non peptide thrombin inhibitors.). Med.
`C/11~111., 45 , 1757- 1766.
`19 Eikelboom, J. W. :md Weitz, J. l. (2010)
`Update on antithrombotic therapy. New
`anticoagu lants. Cirwlat.ion, 121, 1523- 1532.
`20 Black, J.W. and Stephenson, J.S. (1962)
`Pharmacology of a new adrenergic beta(cid:173)
`receptor-blocking compound . Lancet., 2
`(7251 ), 311 - 314.
`
`Page 18 of 20
`
`

`
`1sl 1 Pioneer and Analogue Drugs
`
`21 Black, J.W., Crowther, A. F. , Shanks, R.G.,
`Smith, L.H. , and Dornhorst, A.C. (1964) A
`new adrenergic beta-receptor antagonist.
`Lancet. 1 (7342), 1080-1081.
`22 Barrett, A.M., Ca rter, )., Fitzgerald, J.D.,
`Hull, R., and LeCoun t, D. (1973) A new
`type of card ioselcctive adrenoceptivc
`blocki ng drug. Br. ). Pharmacal.. 48, 3408.
`23 Flick, K., Frankus, E .. and Friderichs, E.
`(1978) Studies of chemical structure and
`ana lgetic activity of phenyl substituted
`aminomethylcyclohexanoles. Arzn~irn.­
`Forsch.jDrug Res., 28 (1), 107- 113.
`24 Buschmann, H., Strassburge r, W. , and
`Fridcrichs, F. (2001) 1-Phe nyl-3-
`dirnethylaminopropane compounds with
`a pharmacological effect. EP 693 475 .
`25 Schmutz, J. and Eichen be rger, E. (1982)
`C lozapinc, in Chronicles of Drug
`Discoveries, vol. 1 (eds J.S. Bindra and D.
`Led nice r) , john Wi ley & Sons, Inc.,
`New York, pp. 39-60.
`26 Szegedi, A., Wiesner,) .. Hillert, A.,
`Hammes, E., Wetzel, H ., and Benkert, 0 .
`(1993) IC I 204,636, a putative "atypical"
`anti psychotic, in the treatment of
`
`schizophrenia with positive
`symptomology: a n open clinical trial.
`Pharmacopsychiatry. 26, 197.
`27 Kuhn, R. (195 7) Uber die Bchandlung
`de pressiver Zustande mit einem
`lminodibenzyl De rivat {G 22355).
`Schw~iz. Med. Wochmsch. , 87, 1135.
`28 Montgomery, S.A., McAu ley, R., Rani, S. J.,
`Roy, D. , and Montgomery. D. B. (1981 ) A
`double bli nd comparison ofzimelidinc
`and amitriptyline in endogenous
`depressio n. Acta Psychiatr. Scand. Suppl.,
`290, 314-327.
`29 Wong, D.T, Horng, J. S., Bymaste r, F.P.,
`Hauser, I<.L., and Ma lloy, B. B. (1974) A
`selective inhibitor of serotonin uptake:
`Lilly 110140, 3-(p-triAuoromethylphenoxy)(cid:173)
`N-methyl- 3-phenylpropylamine. Lij~ Sci.,
`15, 471-479.
`30 Bigler, A.J., Bt1gesu, K.P., Toft, A., and
`Hansen, V. (1977) Quantitative structure(cid:173)
`activity re lationships in a seri es of
`selective 5-HTuptake inhibitors. Eur.).
`Med. Cl-1~m. , 12, 289-295.
`
`Page 19 of 20
`
`

`
`References 119
`
`Janos Fischer is Senior Research Scientist at Ri chter Plc.
`(Budapest, Hungary). He received hi s ed ucation in Hungary
`with M.Sc. and Ph.D. degrees in Organic Chemistry from
`Eotvos University of Budapest with Professor A. Kucsman.
`Between 1976 and 1978, he was a Humboldt Fellow at the
`University of Bonn with Professor W. Steglich. He has
`worked at Richter Plc. since 1981, where he participated in
`the research and development of leading cardiovascular
`drugs in Hungary. His main current interest is analogue(cid:173)
`based drug discovery. He is author of some 100 paten ts and
`scientific publications. In 2012, he was reelected Titular Member of the Chemistry
`and Human Health Division of IUPAC. He received an honorary professorship at
`the Technical University of Budapest.
`
`C. Robin Ganellin studied chemistry at London University,
`receiving a Ph .D. in 1958 under Professor Michael Dewar,
`and was a Research Associate at MIT with Ar