CHAPTER 1

Ion Channel Drug Discovery:a Historical Perspective

BRIAN COX

Global Discovery Chemistry, Novartis Institutes for Biomedical Research,Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UKEmail: brian.cox@novartis.com

1.1 IntroductionIon channels are membrane proteins that control the flow of ions across thecell membrane, are present in the membranes of all cells and make up oneof the two traditional classes of ionophoric proteins along with ion trans-porters. Ion channels are responsible for maintaining resting membranepotential and all electrical signaling; they play a key role in the modulationof intracellular calcium levels crucial for the regulation of many cellularfunctions events and consequently a fundamental role in many physiologicalprocesses.

Ion channels are classified in a number of ways; by gating, i.e. what opensand closes the channels. Voltage-gated ion channels open or close de-pending on the voltage gradient across the plasma membrane, while ligand-gated ion channels open or close depending on binding of ligands to thechannel. Further classifications are by the ion (or ions) that is (are) con-ducted e.g. sodium, calcium, potassium, proton, chloride or non-selective, orby the duration of the response to stimuli e.g. the transient receptor po-tential channels (TRP channels). Finally, for example in the potassiumchannel superfamily, they are classified by the number of pore loops con-tained in each channel forming subunit. The vast majority of channels form

RSC Drug Discovery Series No. 39Ion Channel Drug DiscoveryEdited by Brian Cox and Martin Goslingr The Royal Society of Chemistry 2015Published by the Royal Society of Chemistry, www.rsc.org

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as tetramers of subunits that each contributes a single pore loop to theion-conducting pore; however, there is a small family of two-pore-domainpotassium channels (K2P), where channel subunits have two pore loopseach; channels are formed as dimers of these subunits.1

In the same way as ‘‘kinome’’ is used to describe the protein kinase familyof enzymes within the genome, the term ‘‘chanome’’ or ‘‘channelome’’ isoften used to describe the 4300 members of the ion channel family as-sembled from the B500 annotated ion channel proteins as predicted in thehuman genome. With ion channels being such a large class of targets andinvolved in many key physiological processes it is surprising that less thantwenty percent are currently commercially exploited.

When co-authoring an article on ion channels in 2005,2 examination ofthe marketed ion channel modulators at that time highlighted that themajority of ion channels targeted up to that point had almost exclusivelybeen ligand- or voltage-gated channels found in excitable tissues such asnerve and muscle. Since then there has been a number of drugs entering themarket: retigabine (1), verenicline (2) and ivacaftor (3), and promisingly aconsiderable number of compounds in phase II/III clinical developmentwith a growing number targeting channels in non-excitable tissues.3

Table 1.1 lists a selection of the marketed ion channel modulators, theiruse and their specific ion channel target. Figure 1.1 illustrates the sustainedcommercial interest in the ion channel area as judged by the number ofpatent filings.

HNO

ONH

F

H2NN

N

NH

1 2

NH

NH

OH

O O

3

1.2 History of Ion Channel Drug DiscoveryClassic examples of early ion channel modulator discovery are the voltage-gated sodium channel blockers used as local anesthetics and anticonvulsantsand the L-type voltage-operated calcium channels blockers (L-VOCCs)

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Table 1.1 Currently marketed ion channel modulators.

Ion channel target Use Drugs

L-type voltage-gated Ca21

channelAnti-hypertensive Amlodipine, Nifedipine,

Isradipine, Verapamil,Diltiazem, Nicardipine

L-type voltage-gated Ca21

channelStroke Nimodipine

L-type voltage-gated Ca21

channelAnti-arrhythmic Verapamil, Diltiazem

N-type voltage-gated Ca21

channelAnalgesic Ziconitide

T-type voltage-gated Ca21

channelAnticonvulsant Ethosuximide

KCNQ2 Kv 7.2 Anticonvulsant Retigabinea

Cardiac voltage-gated Na1

channelAnti-arrhythmic Procainamide, Quinidine,

Lignocaine (aka Lidocaine)Brain voltage-gated Na1

channelAnticonvulsant Phenytoin, Lamotrigine,

CarbamazepineVoltage-gated Na1 channel Local anesthetics Benzocaine, Lignocaine

(aka Lidocaine), ProcaineEpithelial Na1 channel Diuretic AmilorideGABA Cl� channel Anticonvulsant DiazepamNicotinic acetylcholine

receptorNeuromuscular blocker/

muscle relaxantsAtracurium

Nicotinic acetylcholinereceptor

Smoking cessation Vareniclineb

5HT3 Anti-emetic Ondansetron, GranisetronKATP channel Diabetes Tolbutamide,

Glibenclamide, GliclazideCFTR channel Cystic Fibrosis Ivacaftor (VX-770)c

Approvals: a2010; b2006; c2012.

0

100

200

300

400

500

600

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Num

ber o

f Pat

ents

Year

Figure 1.1 Patents filed listing ‘‘ion channel modulator’’ as mechanism of action(2000–2012).Thomson Reuters Cortellist.

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which are still in clinical use many years after their first synthesis. Followingan early understanding of the structural features of the natural productcocaine (4), the local anesthetic benzocaine (5) was synthesized in 1890, thenamylocaine (6) in 1903 and procaine (7) in 1905. This was the start of aclassic age of chemistry-driven drug discovery, optimizing compounds forefficacy and duration in animal models resulting in such compounds asprocainamide (8) and lignocaine (lidocaine) (9).4–6 It was not until the late1950’s that these compounds were shown to ‘‘inhibit’’ purported sodiumchannels which at the time were hypothesized to be integral in nerveimpulse transmission.7

N

O

O

O

O

N

4 5

OO

H2N

OO

O

H2N

N

O

6 7

NH

O

H2N

N

HN

N

O

8 9

In the anticonvulsant field, phenytoin (10), synthesized as a phenobarbi-tone analogue in 1937, was introduced for the treatment of epilepsy followedby carbamazepine (11) in the early 1960’s and lamotrigine (12) in thelate 1980’s. During this research compounds were selected primarilyusing animal models such as the maximal electroshock model in rodents.Later data from electrophysiological experiments on brain slices, incloned channel systems and disposition studies has led to a better under-standing of the mode of action of these compounds,8 resulting in thederivation of anticonvulsant pharmacophore models for sodium channelblockers.9,10

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10 11

HNNH

O

O

N

NH2O N

N N

Cl

Cl

NH2

NH2

12

Many of the anticonvulsant sodium channel blockers find off-label use ina variety of neuropathic pain conditions11 e.g. compound 13 (CNV-1014802)is a compound from a distinct structural class, shown to be anticonvulsant12

and is currently under clinical investigation for neuropathic pain. Thecompound, structurally related to a number of earlier published compounds(e.g. CO 102862 (14)13 and safinamide (15)14) and recent compounds pub-lished by workers at Merck (e.g. 1615) is described as a state-dependent so-dium channel blocker that exhibits potency and selectivity against theNav1.7 channel. This molecule was recently granted orphan-drug desig-nation by the US FDA in July 2013 for the treatment of trigeminalneuralgia.16 Even now we are still to fully understand the precise mode ofaction of these compounds on the nine members of the voltage-gated so-dium channel family (Nav1.1-1.9) that contribute to the range of pharma-cology exhibited (see chapter 5 for an extensive review of the Nav channelfamily).

O

F NH NH2

O

13

O

NH

HN

NH2

O

F

14

O

F NH NH2

O

NN NH2

OCF3

CF3

15 16

The recently discovery of the novel anticonvulsant retigabine (1) followed asimilar retrospective discovery route. Originally synthesized as an analogueof the opioid analgesic and muscle relaxant flupirtine in 1993 by researchersat ASTA Medica, it was found to be anticonvulsant. Mechanistically this was

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explained as the result of modulation of the neuronal ‘‘M current’’. Now withthe benefit of molecular insight, retigabine has been shown to be an acti-vator of Kv7.2 (KCNQ2/3). This is covered in detail in chapter 10.

The discovery of L-type calcium channel blockers and their utility in cor-onary disease occurred by chance in 1963, when it was reported that newcompounds such as the phenylalkyamine (17, later named verapamil)mimicked the cardiac effect of simple calcium withdrawal, diminishingcalcium-dependent high energy phosphate utilization, contractile force andoxygen requirement. In 1969, the term ‘‘calcium antagonist’’ was given anovel drug designation. In an extensive search for other calcium antagonists,a considerable number of substances that also met these criteria wereidentified; in 1975 the first dihydropyridines (e.g. nifedipine (18)) were dis-covered followed by many other members of this class in the followingdecades, including longer-acting compounds such as amlodipine (19). Alsoin 1975, a third class of L-type calcium channel blockers was discovered, thebenzothiazepine class e.g. diltiazem (20).17–19

NH

O

O

O

ONO2

18

O

O

N

O

O

CN

17

N

S

O

O

O

O

N

19 20

NH

O

O

O

OCl

ONH2

Ion channel targets in non-excitable tissues remained virtually unexploredin the early period of research apart from the discovery of the sulfonylureaclass of anti-diabetic agents that modulate the ATP-sensitive potassiumchannels (KATP) in pancreatic cells. The sulfonylureas were synthetic off-shoots from the extensive work on sulfonamide antibacterials which were inturn derived from azo dyes (the dye prontosil was found to be a metabolicpro-drug for sulfanilamide). Janbon and co-workers observed that using the

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sulfonamide isopropylthiadozole (21) to treat typhoid patients caused ahigh incidence of hypoglycemia and at the same time Loubatieres workingwith the compound in dogs found it to have ‘insulin-like’ properties.20

Compounds such as tolbutamide (22) entered the clinic for the treatmentof type-II diabetes in 1956 but are now largely superseded by second-generation agents such as glibenclamide (glyburide) (23).21 Almost 40 yearsafter the discovery of the first compounds, the KATP channel in pancreatic bcells was identified as the molecular target for sulfonylureas,22 and anotherdecade passed before the molecular composition of the pancreatic KATPchannel was identified, a complex of the pore-forming inwardly rectifyingchannel Kir 6.2 and sulfonylurea receptor type 1 (SUR1) regulatorysubunit.23

21 22

S

O

HN

O N N

S

H2N S

O

HN

O NH

O

H2N

23

S

O

HN

O NH

O

HN

O

O

Cl

In the 1970’s and 80’s ion channel research was driven by the pharma-cological discovery and classification of ion channel targets in tissue using avariety of synthetic tool molecules designed from endogenous ligands orpharmacologically active natural products. The discovery of membrane-permeable fluorometric indicator dyes allowed the measurement of intra-cellular calcium levels and membrane potential and the development of thepatch-clamp technique allowed individual ion channel activity to be meas-ured for the first time. Data could therefore be provided that gave kinetic andbiophysical information to aid the design of potent and functionally se-lective agents. The discovery stories associated with the 5HT3 and theneuromuscular nicotinic acetylcholine receptors (nAChRs) have been welldocumented and resulted in a considerable number of therapeutically usefuldrugs, e.g. the antiemetic agent ondansetron (24) by workers at Glaxo (nowGSK)24,25 and the neuromuscular blocking agent atracurium (25) by aca-demic workers at Strathclyde University in collaboration with Wellcome(now GSK).26 The latter was designed from consideration of other bi-quaternary compounds and D-tuborcurarine, an alkaloid from the South

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American arrow poison curare, all used as neuroblocking agents at thatpoint. The elimination of atracurium is not dependent on metabolicbreakdown by esterases, unlike other agents, and was found to be underpolymorphic control thus causing unpredictable duration of muscular re-laxation between patients. Instead atracurium was designed to rely on pHdependent Hoffman elimination, which provided highly predictable onsetand duration of action across patients.

24

N

NNO

25

N+

O

O

O

O

O

O

N+

O

O

O

O

O

O

Natural product research still remains an important source of ionchannel modulators (see chapter 12) either as leads for medicinal chem-istry programs or as drugs in their own right. The recently launched var-enicline (2), a partial agonist of the a4b2 nicotinic acetylcholine receptor,utilized therapeutically in smoking cessation, was designed from (�)-cytisine (26) following observations that it was a partial agonist and an-tagonized the receptor response to its endogenous neurotransmitter,acetylcholine.27

Ν

Ν

ΝΗ

NH

N

N

NH

N

O

=

2 26

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The cone snail peptide ziconotide (27) entered clinical use in the lastdecade for the treatment of severe pain and is a highly potent blocker of theN-type voltage-gated calcium channel. It is delivered as an infusion intothe cerebrospinal fluid using an intrathecal pump system.28 Continuing withthe larger molecule theme, antibodies represent a growing field of researchfor finding ion channel modulators; this subject is covered in chapter 13.

H-Cys-Lys-Gly-Lys-Gly-Ala-Lys-Cys-Ser-Arg-Leu-Met-Tyr-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Arg-Ser-Gly-Lys-Cys-NH21 168 20

15 25

NH

HN

HO

OO

HN

OHO

S

O

SO

OH NH

O

HNOH

NHO

SO

HN

H

HN

NH

NH2

NHO

OHO

NHO

NH

HN O

H2N

S

OH2N

O

S

OHN

O

HN

HN

HN NH2O

NHHO

O

HN

S

O

NHH2N

O

HN O

HN

O

NH

H2N O

HN O

HN NH2

OH2N

S

O

27

1

16

8

20

15

25

In the 1990’s advances in molecular pharmacology enabled the re-combinant expression of channel targets in heterologous cellular back-grounds that could be used in high throughput screening modes. Chapter 2covers the impact and advances in high throughput screening in the ionchannel field. VX-770 (ivacaftor) (3) was approved by the FDA in January 2012for the treatment of cystic fibrosis in patients with the G551D mutation andprobably represents the first marketed compound to be derived from a highthroughput screen hit. This molecule stemmed from work carried out atVertex using cell-based fluorescence membrane potential assays in high-throughput mode to identify potentiators and correctors of CFTR function.Early hits from the potentiator and corrector screens are exemplified bycompounds VRT-422 (28) and VRT-532 (29), respectively.29,30 Workers atGenzyme utilized a similar approach to identify hits such as 30.31

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NH

NH

OH

O O

3

OH

28

NHN

N

N

O

N

NS

Br

O

O

29 30

N

NH

ClO

O

O

Another approach towards the treatment of cystic fibrosis is the blockadeof the epithelial sodium channel (ENaC) with research focusing on topicaladministration into the lung of analogues of the potassium sparing diureticamiloride (31), developed by Merck in the 1960’s.32 Amiloride itself has beenstudied in a number of clinical trials with conflicting results; the lack ofefficacy of amiloride may be due to its short duration of action: it is clearedrapidly from the airways and its effect on lower airway potential differencelasts for only approximately 30 minutes.33 Consequently, research effortshave focused on the design of longer acting analogues; this work is de-scribed in chapter 7. Recently, amiloride has also been shown to be a non-selective inhibitor of acid-sensing ion channels (ASICs) and exhibits amodest effect in rat pain models at high concentrations. Structural modifi-cation has provided more potent analogues, with particular focus on ASIC3as the specific family member targeted for blocking chronic inflammatorypain.34

N

NCl

H2N NH2

O

NH

NH

NH2

31

The ionotropic glutamate receptors (iGluRs) comprising of the AMPA,NMDA and kainate families have received much attention as targets fora variety of CNS disorders with a large number of compounds in clinicaltrial.3 Perampanel (32), a non-competitive AMPA-type glutamate receptor

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antagonist, was recently reported to be well-tolerated and effective inreducing seizure frequency in partial onset epilepsy versus placebo.35

Chapter 6 describes an approach to discovery of allosteric modulators ofthis target where co-crystallization of hits derived from screening with aligand binding domain construct was used to aid structural based design.

N O

N

CN

32

Another family of ion channels that has received much interest over thepast decade is that of the transient receptor potential channels (TRP chan-nels) mentioned in the introduction. They are divided into two groups:group 1 containing the TRPC, TRPV, TRPM, TRPN and TRPA sub-groups andgroup 2 containing the TRPP and TRPML sub-groups. The fascinating pro-spect for modulation of these channels is that they mediate a variety of keybodily sensations such as pain, hot or cold, tastes, pressure, and aspects ofvision.36 The search for antagonists of TRPV1 as potential analgesics hasbeen a major endeavor for many researchers and is covered in chapter 9.

One channel that has received more attention than almost any other is thehERG channel. HERG refers to the human Ether-a-go-go-Related Gene,alternately known as KCNH2, that codes for the potassium channel alphasubunit Kv11.1. This channel is involved in the mediation of the repolarizingcurrent (IKr) in the cardiac action potential. HERG is actually a therapeutictarget with compounds such as dofetilide (33), a class III antiarrhythmicagent, used for the maintenance of sinus rhythm.37 Unfortunately the mainattention has not been for positive reasons but as a target associated withoff-target pharmacology (a so-called ‘‘anti-target’’) manifesting itself as lifethreatening drug-induced long-QT syndrome. Terfenadine (34) is perhapsthe most well-known example, used widely as an antihistamine until reportsof long-QT syndrome prompted its withdrawal. It was found to be a hERGblocker that under normal circumstances was rapidly metabolized byCYP3A4 on first-pass to an active metabolite that did not block hERG.However, many other drugs (e.g. erythromycin) and some foods (e.g. grape-fruit juice) inhibit the function of CYP3A4 thus preventing the metabolism ofterfenadine, leading to accumulation in the plasma and inevitable cardiacside-affects. The active metabolite of terfenadine, fexofenadine (35), is nowmarketed as an antihistamine in its own right and gave a structural insightinto how to avoid hERG affects.38 The structure–activity relationships of

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hERG modulation have been widely studied; a growing pharmacophoricunderstanding and careful pharmacological screening now aid drug designin avoiding hERG associated liabilities.39,40 A full discussion on hERG ispresented in chapter 11.

33

NH

S

O

O

NO

HN

S

O

O

OHN

OH

34

OHN

OH

35

O

OH

Since Rod Mackinnon and Peter Agre received the 2003 Nobel Prize forchemistry for discoveries concerning channels in cell membranes and forthe discovery of water channels, respectively,41 there has been an increasingnumbers of ion channel crystal structures solved, with an expectation thatmany more structures will be determined in the coming years. The form andcomposition of native ion channels has also been under scrutiny and it isclear now that ion channels are not isolated ion-conducting pores but areintegral components of structural and signaling complexes in cells. They donot just function in isolation but have closely associated accessory scaf-folding sub-units and proteins, which are important for the functionality ofthe native channel, not only in terms of activation but also in terms of en-suring correct assembly, trafficking, insertion and retrieval.42 Chapter 4gives further insights into the study of ion channel structure.

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Despite the availability of cellular systems containing cloned channeltargets and the growing amount of information regarding ion channelstructure and function, the pursuit of ion channel targets in high through-put screening mode has not progressed as well as other target classes, suchas GPCRs and enzymes. Often screens use indirect assay readouts, such asion-sensitive and potentiometric dyes, radiotracer flux and binding assays;although much higher throughput, all have well-documented limitations,such as sensitivity and a high potential for false positives.43 Electro-physiology represents the highest fidelity option for ion channel screening,but was exceptionally low throughput, time consuming and required tech-nically skilled operators. However, the advent of automated electro-physiology offers the opportunity of running direct electrophysiology-basedHTS campaigns; this is covered in chapter 3.

1.3 ConclusionIon channel research has come a long way in the last 100 or so years, pro-viding a wealth of novel and important medicines for the clinic. Continuingscientific and technological advances in the field of screening, structural-based design, the increasing chemical space of modulators available (lowmolecular weight, peptides, antibodies etc.) coupled with the availability ofgenetic information, raises the exciting prospect of taking us into a newmore predictive and hopefully productive era of ion channel drug discovery.

AcknowledgementMany thanks to Andrew Davis for carrying out the searches to provide thedata expressed in Figure 1.1.

References1. Z. Es-Salah-Lamoureux, D. F. Steele and D. Fedida, Trends Pharmacol.

Sci., 2010, 31(12), 587.2. S. Li, M. Gosling, C. T. Poll, J. Westwick and B. Cox, DDT, 2005,

10(2), 129.3. A. Wickenden, B. Priest and G. Erndemli, Future Med. Chem., 2012,

4(5), 661.4. R. Sabatowski, D. Schaefer, S. M. Kasper, H. Brunsch and L. Radbruch,

Curr. Pharm. Des., 2004, 10(7), 701.5. J. Wojnar, Chem. N. Z., 2007, 71(1), 20.6. W. O. Foye, in Foye’s Principles of Medicinal Chemistry, ed. D. A. Williams

and T. L. Lemke, Lippincott, Williams & Wilkins, Philadelphia, PA, 2002,p. 4.

7. S. Stolc, Gen. Physiol. Biophys., 1988, 7, 177.

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8. C. H. Large, M. Kalinichev, A. Lucas, C. Carignani, A. Bradford,N. Garbati, I. Sartori, N. E. Austin, A. Ruffo, D. N. C. Jones, G. Alvaro andK. D. Read, Epilepsy Res., 2009, 85, 96.

9. K. Unverferth, J. Engel, N. Hofgen, A. Rostock, R. Gunther, H. J. Lankau,M. Menzer, A. Rolfs, J. Liebscher, B. Muller and H.-J. Hofmann, J. Med.Chem., 1998, 41(1), 63.

10. G. M. Lipkind and H. A. Fozzard, Mol. Pharmacol., 2010, 78(4), 631.11. T. S. Jensen, Eur. J. Pain, 2002, 6(Suppl. A), 61.12. C. H. Large, S. Bison, I. Sartori, K. D. Read, A. Gozzi, D. Quarta,

M. Antolini, E. Hollands, C. H. Gill, M. J. Gunthorpe, N. Idris, J. C. Neilland G. S. Alvaro, J. Pharmacol. Exp. Ther., 2011, 338(1), 100.

13. V. I. Ilyin, D. D. Hodges, E. R. Whittemore, R. B. Carter, S. X. Cai andR. M. Woodward, Br. J. Pharmacol., 2005, 144, 801.

14. Drugs R D, 2004, 5(6), 355.15. S. Tyagarajan, P. K. Chakravarty, B. Zhou, B. Taylor, M. H. Fisher,

M. J. Wyvratt, K. Lyons, T. Klatt, X. Li, S. Kumar, B. Williams, J. Felix,B. T. Priest, R. M. Brochu, V. Warren, M. Smith, M. Garcia,G. J. Kaczorowski, W. J. Martin, C. Abbadie, E. McGowan, N. Jochnowitzand W. H. Parsons, Bioorg. Med. Chem. Lett., 2010, 20(18), 5480.

16. http://www.convergencepharma.com/.17. A. Fleckenstein, Circ. Res., 1983, 52, I3–I6.18. M. Harrold, in Foye’s Principles of Medicinal Chemistry, ed. T. L. Lemke

and D. A. Williams, Lippincott, Williams & Wilkins, Philadelphia, PA,2013, p. 768.

19. W. M. Yousef, A. H. Omar, M. D. Morsy, M. M. Abd El-Wahed andN. M. Ghanayem, Int. J. Diabetes & Metabolism, 2005, 13(2), 76.

20. H. Kleinsorge, Exp. & Clin. Endocrinol. & Diabetes, 1998, 106(2), 149.21. S. W. Zito, in Foye’s Principles of Medicinal Chemistry, ed. T. L. Lemke and

D. A. Williams Lippincott Williams & Wilkins, Philadelphia, PA, 2013,p. 890.

22. N. C. Sturgess, R. Z. Kozlowski, C. A. Carrington, C. N. Hales andM. L. J. Ashford, Br. J. Pharmacol., 1988, 95(1), 83.

23. S. Seino, Annu. Rev. Physiol., 1999, 61, 337.24. R. Barrett, D. Cavalla, I. H. Coates, C. Eldred, G. B. Ewan, N. Godfrey,

D. C. Humber, P. C. North and A. W. Oxford, in Trends Med. Chem. ’90,Proc. Int. Symp. Med. Chem. 11th, ed. S. Sarel, R. Mechoulam andI. Agranat, Blackwell, Oxford, 1992, p. 107.

25. Y. Chong and H. Choo, Expert Opin. Investig. Drugs, 2010, 19(11), 1309.26. R. D. Waigh, Chem. Br., 1988, 24(12), 1209.27. J. W. Coe, P. R. Brooks, M. G. Vetelino, M. C. Wirtz, E. P. Arnold,

J. Huang, S. B. Sands, T. I. Davis, L. A. Lebel, C. B. Fox, A. Shrikhande,J. H. Heym, E. Schaeffer, H. Rollema, Y. Lu, R. S. Mansbach,L. K. Chambers, C. C. Rovetti, D. W. Schulz, F. D. Tingley III andB. T. O’Neill, J. Med. Chem., 2005, 48, 3474.

28. H. E. Hannon and W. D. Atchison, Mar. Drugs, 2013, 11, 680.

14 Chapter 1

Dow

nloa

ded

on 1

1/09

/201

4 12

:58:

42.

Publ

ishe

d on

03

Sept

embe

r 20

14 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/978

1849

7350

87-0

0001

View Online

29. F. Van Goor, K. S. Straley, D. Cao, J. Gonzalez, S. Hadida, A. Hazlewood,J. Joubran, T. Knapp, L. R. Makings, M. Miller, T. Neuberger, E. Olson,V. Panchenko, J. Rader, A. Singh, J. H. Stack, R. Tung, P. D. J. Grootenhuisand P. Negulescu, Am. J. Physiol. Lung Cell Mol. Physiol., 2006, 290, L1117.

30. F. Van Goor, S. Hadida, P. D. J. Grootenhuis, B. Burton, D. Cao,T. Neuberger, A. Turnbull, A. Singh, J. Joubran, A. Hazlewood, J. Zhou,J. McCartney, V. Arumugam, C. Decker, J. Yang, C. Young, E. R. Olson,J. J. Wine, R. A. Frizzell, M. Ashlock and P. Negulescu, Proc. Natl. Acad.Sci. U. S. A., 2009, 106(44), 18825.

31. B. H. Hirth, S. Qiao, L. M. Cuff, B. M. Cochran, M. J. Pregel, J. S. Gregory,S. F. Sneddon and J. L. Kane, Jr, Bioorg. Med. Chem. Lett., 2005,15(8), 2087.

32. E. J. Cragoe, Jr, O. W. Woltersdorf, Jr, J. B. Bicking, S. F. Kwong andJ. H. Jones, J. Med. Chem., 1967, 10(1), 66.

33. H. C. Rodgers and A. J. Knox, Eur. Respir. J., 2001, 17(6), 1314.34. S. D. Kuduk, C. N. Di Marco, R. K. Chang, R. M. DiPardo, S. P. Cook,

M. J. Cato, A. Jovanovska, M. O. Urban, M. Leitl, R. H. Spencer,S. A. Kane, M. T. Bilodeau, G. D. Hartman and M. G. Bock, Bioorg. Med.Chem. Lett., 2009, 19(9), 2514.

35. S. Rheims and P. Ryvlin, Neuropsychiatr. Dis. Treat., 2013, 9, 629.36. Transient Receptor Potential Channels. Advances in Experimental Medicine

and Biology, ed. M. S. Islam, Springer, Netherlands, 2011.37. H. Roukoz and W. Saliba, Expert Rev. Cardiovasc. Ther., 2007, 5(1), 9.38. I. Paakkari, Toxicol. Lett., 2002, 127(1–3), 279.39. M. Recanatini, E. Poluzzi, M. Masetti, A. Cavalli and F. De Ponti, Medi-

cinal Research Reviews, 2005, 25(2), 133.40. E. Raschi, V. Vasina, E. Poluzzi and F. De Ponti, Pharmacol. Res., 2008,

57(3), 181.41. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/.42. C. Deutsch, Neuron, 2003, 40(2), 265.43. J. Xu, X. Wang, B. Ensign, M. Li, L. Wu, A. Guia and J. Xu, DDT, 2001,

6(24), 1278.

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