/The Organic Chemistry of
`Drug Design and Drug Action/
`
`Richard B.\\Si|verman
`Department of "Chemistry
`Northwestern University
`Evanston, Illinois
`
`ACADEMIC PRESS
`A Divisiarl of Harcourt Brace & Company
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`
`MYLAN - EXHIBIT 1013
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`MYLAN - EXHIBIT 1013
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`Copyright
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`1992 by ACADEMIC PRESS
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`Academic Press
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`tjitrd Kingdom Ediiw FlthIished by
`Acade ac Press Lint eel
`2428 Oval Road London NWI 7DX
`
`di aryof Cm gresa Catalog og-in-Pub Ic tie Data
`
`Si vnaar RkluardB
`The urgerie cheruatry of drug design and drug acts
`Silverman
`
`Re ised
`
`Includes
`index
`ISBN 5126437308 hardcover
`Pharmaceutical
`
`chensiatsy
`
`Bioorgarnc etemistry
`
`Drugs- Design
`Molecular pharmacology
`DNLM
`Cbcmlstiy Organic
`Ciemsstr Pharmaceutical
`QV 744 S587oJ
`Drug Desig
`Phannacokinetirs
`R5403.S53
`
`Title
`
`1992
`
`613 ltr.dclO
`DNLIMLC
`to
`
`ibnarvolCoigress
`
`Fr 4rl
`
`tle
`
`radS
`
`iv
`
`47041
`
`UP
`
`

`
`CHAPTER
`
`Drug Discovery Design
`and Development
`
`__
`
`Drug Discovery
`Drug Discovery without
`Librium
`Pen
`Ihus
`cad Discovery
`Ruidom
`enmg
`Clinknl Causervaunus
`
`ad
`
`Noncindom Scrrn ng
`Drug Mctabolisr Studies
`kariona App oahes an Lead La-
`ruver
`Id
`
`IL Drug Deve1opment Lead Modification
`Identification of thc Active Part Thc Pharmacophore
`13 Functional Group Modthcation
`13
`
`11
`
`ructuteActivaty Relationships
`Structure Modifications to Increase Potcn
`ham Branchin
`
`Homokaga ion 16
`Bini otermm 19
`
`14
`
`18
`
`and therapeutic Index
`Rm Liam tr usformat ons 18
`
`15
`
`Quanttatave StructureActivity Relationships
`Physico hemica
`ameters 24
`Historical
`23
`ochemc
`Phy
`Paraireters with Biological Acti
`Mthods
`QSAR Related to Rec pior Band ug 43
`Molecular Graphic Bascd Drug Dcsigai
`44
`47
`Fpilogue
`
`Rcference
`
`Genetal Reterences
`
`50
`
`23
`
`sed to CorreLtc
`Methods
`Computer Besd
`
`Drug Discovery
`
`In general clinically used drugs are not discovered What
`is more likely
`discovered is known as
`lead compound The lead is
`prototype compound
`that has the desired biological or pharmacological activity but may have
`for example high toxicity other bio
`many other undesirable characteristics
`logical ctivltis insolukiht or wetabolFsm problem The structure of the
`lead compound is then modified by synthesis to amplify the desircd activity
`and to minimize or eliminate thc unwanted properties Prior to an ehiboration
`of approaches to lead discovery and lead modification two of the rare drugs
`discovered without
`lead are discussed
`
`

`
`Drug Discovery
`
`Drug Discovery without
`
`Lead
`
`Fenicilhins
`
`culture of
`
`this
`
`grecn mold growing in
`In 1928 Alexander
`leming noticed
`StaphyIococcw aureu and where thc two had convcrged
`the bacteria were
`lysed This led to the discovcry of penicillin which was produced by the
`mold It may be thought
`this observation was madc by other scientists
`that
`who just ignored it and therciore Fleming was unique for following up on it
`Howevei
`the case Fleming tried many times to rediscover
`this is not
`phenomenon without success it was his colleaguc Dr Ronald Hare23 who
`was able to reproduce the observation It only occurred the first
`tune because
`took place simultancously Hare found
`combination of unlikely cvents all
`that very special conditions were required to produce thc phenomenon ini
`tially observed by Fleming The culture dish inoculated by Fleming must have
`become accidentally and simultaneously contaminated with the mold spore
`Instead of placing the dish in the ref ngerator or incubator when he went on
`vacation as is normally done Fleming inidveitently left
`it on his lab bench
`When he returned the following month he noticed the lysed bacteria Ordi
`narily penicillin does not lyse these bacteria it prevents them from develop
`if added after the bacteria have developed However
`ing but it has no effect
`lemmg was on vacation July to August
`the weather was unseason
`whale
`ably cold and this provided the particular temperature required for the mold
`and the staphylococci
`to grow slowly and produce the lysis Another extraor
`dinary circumstance was that the particular strain of the mold on
`Jemings
`culture was
`relatively good penicillin producer although most strains of that
`mold PniciI1ium produce no penicillin at all
`he mold presumably came
`from the laboratory just below Flemings where research on molds was going
`on at
`the time
`Although Fleming suggested that penicillin could he useful as
`topical
`antiseptic he was not successful
`form suitable to
`in producing penicillin in
`treat infections Nothing more was done until Sir Howard
`lorry at Oxford
`University reinvestigated the possibility of producing penicillin in
`useful
`form In 1940 he succeeded in producing penicillin that could be administered
`topically and systemically4 but the full extent of the value of penicillin was
`the late l940s Iwo reasons for the delay in the universal
`revealed until
`utilization of penicillin were the en ugence of the sulfonamide intabacterials
`sulfa drugs LI see Chapter
`Section IV 131 in 1935 and the outbreak of
`World War
`The pharm icology production and clinical application of
`this wonder drug would
`pcmeiflin were not revealed until after the war so that
`
`ii
`
`SO2NHR
`
`

`
`Drug Discovery Dc ign 6nd Deve opment
`
`team of Allicd scientIsts vho wer interrt ga
`not be used by the Germans
`rng Uciman scicntists invoved in chemothciapeutic
`rcscaich wcre told that
`report of penicillin wis mad usr lot co nmer
`thc Liermans thought
`inc initial
`reasons to coi
`ipete with the sulfa drugs
`take the report
`hey did not
`
`ci
`
`seriously
`he original mold was Penkilhum nc zaiwn
`strain that gave
`relatively
`tow yield of penicillin It was replaced by Pc mc iiiim hry
`aiim which
`had been cultured horn mold growing on
`in market in Peoria
`grapefruit
`Illinois the correct structure of penicillin 22 was elucidated in 1943 by Sir
`Robert Robinson Oxford and Karl olker Merck Several different penn
`these 22
`gioup varied were isolated early on only two of
`cillin analogs
`CL Ph penicillin Gj are still
`PnuCIl2 penicitlin
`and 2.2
`in use
`today
`
`11
`
`22
`
`cit
`
`OI
`
`Eibrium
`
`he first
`
`chloro methy1
`ibrium
`rzodiaiepine tranquill7u drug
`phenyl-3111 4-benzodIazepine 4oxide 2.33 was discovered seren
`arnino
`en Sternbach at Roche was involved in
`dipitously Dr
`program to synthe
`new class of tranquilizer drugs He originally set out to prepare
`size
`series
`of benzhcptoxdiazines 2.4 but when
`NR2 and R2 was C6H5 it
`was
`oxide 2.S
`was found that
`the actual stiucture was that of
`quinazolme
`However none of
`these compounds gave any interesting pharmacological
`results The program was abandoned in 1955 in order br Sternbach to work
`In 1957 during
`on
`different project
`laboratory cleanup
`general
`CH NICH3 R2
`Cl R1
`containing what was thought
`to be 2.5
`C6H1 was found and as
`last effort was submitted for pharmacological
`the other compounds submitted this one gave very promis
`alike all
`testing
`tests used for preliminary screening of tranquilizers
`ang results in six different
`
`vial
`
`ci
`
`2.3
`
`j2
`
`2.4
`
`2.5
`
`

`
`NH
`
`Drug 015 overy
`
`CI
`
`2Ai
`
`HNH
`
`NH113
`
`CI
`
`10
`
`NHH
`
`_j1
`11
`
`23
`
`Scheme 2i Mecharnsm for torr aton of
`
`bruim
`
`the compound was not
`Further investigation revealed
`that
`quinaioline
`uhcr was the beniodiaieprnc
`oxide Z.3j presumably pro
`3-oxide out
`duced in an uncxpccted
`reactLon of the eorrcsponding chioromethyl quinaio
`line 3-oxide 2.6 with methylamine Schemc
`If this coirpound had not
`been found in the taboratory cleanup all of the negative pharmacological
`results would havc bccn reportcd for thc quinaoline
`oxide class of corn
`oxidcs may not have been disoovcrcd for rnan
`and benzodiazepine
`pounds
`years to ornc
`lead are quite few in number
`he cxamples of drug discovery without
`The typical occurrence is that
`lead compound is identified and its structure
`is modified to give eventually the drug that goes to the clinic
`
`Lead Discovery
`
`Penicillin
`
`and Labiiurn are inde4ed two important drugs that were discov
`they then became
`Lead Once they were id ntthed however
`ered without
`here are now myriad of penicillin-
`lead compounds for future analogs
`derived aritibacterrals that have been synthesized as the result of the structure
`tdiazepam 2.7 was synthesized
`etucidarion of rhc earliest penicillins \aliur
`at Roche even before Librium was introduced on to the market
`this drug was
`derived from the lead compound
`and is almost 10 ti nes note potent
`than the lead
`
`

`
`gr
`
`Dy
`
`proart
`
`27
`
`ry
`
`ii
`
`und
`
`Ii
`
`in
`her
`
`for
`
`ste
`
`relati
`
`to
`
`activi
`
`and
`
`st
`
`elic ii
`
`etv cci
`
`is
`
`ci not
`
`thc diheul
`KroI
`arisc
`sc
`in
`it scveial appro cites tt at can tx ker
`ad
`icier tify
`for all of the approaches is to has
`ay compound
`mear
`requirement
`whe
`it will be kro
`particular biokwi al
`cc nporind
`ictivity so hr
`ans of terr nin
`SQ or eree
`Is achy
`hi IogIcaI
`vhtFc
`ontiol cot pound
`en np rind ias the desire
`iv
`of he euripo nd is Note tie
`vhat tie it
`the terms act
`the
`licular
`zy
`ffv
`
`ulsan
`
`tivi
`
`pt armacological
`urt
`
`oh
`the hr rtt of tE
`tests
`begin as
`ret eptor others
`to prevert an rduced seilu
`uu ker and less cx
`va ely of ppro ehes to de rof
`
`reer
`nta
`tic
`
`Cur
`
`tie
`
`are
`
`ipu mci
`tets
`
`Random Screening
`
`p1
`
`It
`
`On
`
`dci
`
`ac iv
`
`Ci
`
`icc
`
`elf
`
`Sort
`
`nhi
`
`it
`
`ts for
`
`in
`
`says or
`or
`ci yr
`tie ability
`
`It
`
`ncr
`ti
`de ekiivd
`
`ad
`
`Randa ii
`irvolves no mId eemal ation alit
`trir
`npou id arc ested ii
`the di ens ry of
`the ooa say vithout regard to titer sIt ietures Poor to 1935
`sulfa ci ugs random screening Wa
`tally lit oni approaeh today this
`esser
`ci to 1eer Jegre Howe
`dora seenng programs are
`method
`11 order to
`leads that has
`seover drugs
`still very important
`imexpected
`and unusual
`tnictu Cs fo various targets
`two major classes
`reene
`nate ral
`tie yntheire
`ianne An
`ant and
`tural prod let
`xau Ic of
`rerobi ii
`creen
`ci na oral mpour ci
`is he
`syn ietie
`orgies aid th Nat anal Cancer
`nst tu
`cot pa nd
`mit
`ret ned ii
`cci drug re tilted fiat
`anti
`ij
`nn
`vqv
`
`hen ais and
`odour
`
`ar or
`
`icer
`
`ii
`
`th
`
`sic
`
`au
`
`19
`bio ssay
`
`declared
`Ary ne
`ew
`
`frogs
`
`nf
`
`ci
`
`th
`
`tFe
`
`set
`
`icr
`
`rio
`
`Ut
`
`ci
`
`Ti
`
`Ic
`
`are no
`
`utili
`
`cci
`
`In
`
`1940s
`
`ci
`
`tout plc hi
`cc
`by
`
`anti
`
`11
`
`ay
`it us ph
`
`iii
`
`ci
`
`in
`aken
`in
`ci Fuutwo mp rtant
`acisu eo
`dine were foun
`
`euti
`
`eomp
`case
`
`of soil
`
`ii
`
`as
`
`randon
`
`950
`aid
`
`iI
`
`eros
`
`hr rlonyein
`
`citi
`
`clii
`
`

`
`Drug Discovery
`
`Nonrandom Screening
`
`than is random
`slightly more narrow approach
`Nonrantlom 3crenüig is
`saue reenh1ance to weakl
`screening In thi casc compounds has lug
`random sercerl or compounds containing
`activt compounds uncovered
`in
`functional groups than leads may Lx tested selectively By the late
`different
`1970s the National Cancer Ins titutcs random screen was modified to
`non
`random screen because of budgetary and rnanpowcr restrictions Also the
`single tumor screen was changed to
`variety of tumor screens as it was
`realized that cancer
`is not just
`single disease
`
`Drug Metabolism Studies
`
`During metabolism studies drug mezabolites drug degradation products gen
`crated in viva that are isolated are screened in order to determine if
`the
`activity observed is derived from the drug candidate or from metabolite For
`example the anti rnflammatory drug sulindac 2.S is not
`the active agent the
`metabolic reduction product 2.9 is rcsponsible for the activity
`classic
`example of this approach is thc discovery of the antibacterial agent sulfanii
`amide 2J
`which was found to be metabolite of prontoil 2.10
`Section IVB1 for details
`see haptcr
`
`OH
`
`2.8
`
`NH
`
`4H1
`NN
`
`2.10
`
`SONI12
`
`Clinical Observations
`
`trials will exhibit more
`Often
`drug candidate during animal testing or clinical
`is it may produce
`than one pharmacological activity that
`Ihis
`side effect
`compound then can bc used as
`lead for the secondary activity
`antihistamine dimenhydrinate 2.11 Dramamine was tested at
`the allergy
`clinic at Johns Hopkins University and was found also to be effective
`
`In 1947 an
`
`in
`
`

`
`10
`
`Drug Di ovory
`
`agn and Dev opr ert
`
`patient who suffered from car sickness
`further study proved its
`relieving
`is now the
`effectiveness in the treatment of seasickness9 and airsickness
`forms of noton sin
`mot idely used Jiug for th treatment of all
`An antibacterial agent car butamide 212
`NH
`was found to have an
`antidiabetic side effect However it could not be us
`as an antidiabetic drug
`then was
`because of its antibacterial activity Carbutamidc
`lead for the
`discovery of tolbutamide 2J2
`CH3 an antidiabetic drug without anti
`bacterial activity
`
`It
`
`Ph
`
`11
`
`211
`
`Cu
`
`SO2NF CNH
`
`212
`
`Rational Approaches to Lead Discovery
`
`None of the above approaches
`to lead discovery involves
`major rational
`component The lead is just found by screening techniques as
`by product of
`drug metabolism studies or from whole animal investigations Is it possible to
`compound having
`particuLr activity Rational apprrache to drug
`design
`design have now become the major routes to lead discovery The first step is
`to identify the cause for the disease state Most diseases or at
`the
`least
`symptoms of diseases arise from an imbalance of particular chemicals in the
`body from the invasion of
`foreign organism or from aberrant cell growth
`As discussed in later chapters the effects of the imbalance can be corrected
`receptor see Chapter
`by antrgonism or agonisru of
`or by inhibition of
`particular enzyme see Chapter
`Foreign organism enzyme inhibition and
`interference with DNA biosynthesis or function see
`are also im
`hapter
`to treat diceise ariing frnm nuicrnorganisrn and aher
`porthnt approaches
`rant cell growth
`Once the relevant biochemical system is identified lead compounds
`then
`become the natural receptor agonists or enzyme substrates For example lead
`compounds for the contraceptives norgestrel 2.13 and 7c-ethynylestra
`diol 214 were the steroidal hormones progesterone 215 and 17/3 estradiol
`
`c_H HI
`
`OH
`
`OH
`
`CE
`
`c_H HO-C
`
`213
`
`214
`
`

`
`Drug Deveopment Lead Mod1cabon
`
`11
`
`2.16 Whcreas
`the steroid hormoncs 2.15 and 2.16 show weak and short
`lastmg effects the oral contraceptives 2.13 and 2i4 exert stlong progesta
`tional activity of long duration
`
`OH
`
`JJCJ1t$
`
`15
`
`216
`At Merck it was believed that serotonin 217 was
`possibk mcdrator of
`inflammation Consequently serotoiun was used as
`lead for antiinflamma
`tory agents and from this lead the antiinflammatoiy drug indomcthaein 2.18
`was developed
`
`HO
`
`NH
`
`217
`
`OH
`
`Jo
`
`18
`
`The iationai approaches are directed at
`as not possible
`lead discovery It
`toxicity and sidc cifects anticipate transport
`with much accuracy to foretell
`fate of drug Once
`the inctabohc
`or predict
`lead is adcnti
`characteristics
`tied its structure can be modified until an effective drug is prepared
`
`II Drug Development Lead Modification
`
`Once your lead compound is in hand how do you know what
`order to improve the dcsircd ph umacological propea ties
`
`to modify in
`
`Identification of the Active Part The Pharmacophore
`
`hcre
`Interactions of drugs with receptors ire very specific see
`hapter
`small part of the lead compound may be involved in the appropn
`tore only
`the relevant groups on molecule that interact with
`ate interactions
`recep
`
`

`
`12
`
`Drug Discovery Des gn and Dave oprnent
`
`known
`tor and are rcsponsible for the activity are collectively
`as the
`pharma opJqj If the lead compound has additional groups they may inter
`with the appropriate interactions One approach to lead modification
`to
`cut away sections of the molecule in order to determine what parts are essen
`tial and which are superfluous
`As an example of how molecule can be trimmed and still
`result in in
`creased potency or modified activity consider the addictive analgetics mor
`phine 2J9
`CH3
`codeine 2.19
`and heroin
`COCH3 The pharmacophore is darkened If
`the dihydrofuran
`oxygen is excised morphinan 220
`results the hydroxy analog
`OH is
`levorphanol3 2.20
`times more potent than morphine as an
`to
`analelic but it rctdin the addictive properties Removal uf half of the eyIo
`hexene ring leaving only methyl substituents gives benzomorphan 2.21
`CH34 This compound shows some separation of analgetic and addic
`Live effects cyclazocine 221
`CH2
`and pentaiocme
`HCH
`are analogs with much lower addiction liabilities Cutting
`113
`away the cyclohexane fused ring L22 also has little effect on the analge tic
`activity in animal tests Removal of all fused rings for exampk in the case of
`mependine 223 Dcmerol1 gives an analgetic still possessing lOl29 of the
`overall pote ey of morphiue Even acyche analogs are active Dextropro
`cukn it
`poxyphcne 2.24 Ddrvun
`iz onehalf to twothirds as putvnL
`activity can be ascribed to the fact that it can assume
`conformation related
`to that of the morphine pharmacophore Another acyclac
`inalog as methadone
`2.25 which is as potent an analgetic as morphine the
`isomer is used in
`the treatment of opiord abstinence syndromes in heroin abusers
`
`CH3
`
`219
`
`\H
`
`113
`
`OH
`
`22O
`
`2.21
`
`2.22
`
`CF3
`
`113t1
`
`2.23
`
`2.24
`
`2.25
`
`

`
`Drug Deve opment Lead Modificabon
`
`13
`
`In some cases an increase in structural complexity and or rigidity can lead
`to increased potency or example an onpavine derivative such as ctorphiine
`H7 which has
`CH
`2.26
`two carbon bridge and ubstituent
`than morphine and there
`in morphine is about 1000 times more potent
`not
`fore is used in veterinary rnedicinc to immobilize lane anrma1s Fhe related
`CHz-
`analog buprenorphine 226
`ten Bu double bond re
`duced is 1020 times more potent
`very low level of
`than morphine and has
`rigidity of the oripavine do
`Apparently the additional
`dependence liability
`rivatives increases the appropriate receptor interactions see Chapter
`Once the pharmacophore is idcntified manipulation of functional groups
`becomes consequential
`
`HO
`
`228
`
`Functional Group Modification
`
`The importance of functional group modiheation was seen in Section 184
`the amino group of carbutainide 212
`NH2 was replaced by methyl
`Cl3 and in so doing the antibacterial
`group to give toEbutamide 2.12
`In some cases an
`activity was separated away from the antidiabetic activity
`experienced medicitni chemist knows what functional group will elicit
`par
`ticular effect ChkrthiaziJc 227 is an antihpcrtensie agent
`that has
`strong diuretic increased urine excretion effect as well It was known from
`suilTanilamide woik that
`the sulfonamide side chain can give diuretic activity
`see Section IIC Consequently diazoxide 2.28 was prepared as an antihy
`pertensive drug without diuretic activity
`There obviously is
`relationship between the molecular structure of
`compound and its activity This phenomenon was first realized Over 120 years
`ago
`
`I\1
`
`NH SO
`
`NH
`
`00
`
`Ci
`
`NH
`
`2.27
`
`2.28
`
`1i
`
`

`
`14
`
`ry
`
`Deve
`
`pr ent
`
`StructureActivity Relationships
`
`Ii 1b rum Brown ard Iraser
`tFat II
`quatc
`ry
`uspccti
`it mu ular ar ync
`ira may bc esponsitlc ft
`nina ucctJlar bloc mg flEect
`cxamincd
`ty
`of
`quitermied dksk ad
`nary ama oniu
`urnal
`salts
`in
`aes they concludcd that th physioloica acti in of
`naolec
`its chcmacal
`onstatution Shortly thcrcafter Rick ards
`of
`their mo cular
`activity of ahphatic alcohols was
`hypnoti
`tacit of
`fur
`wught Thcs ohs rvations are thc basis for iutur stru tare activity relation
`ships SAR
`1rugs can he classified as being structurally specific or stru turally non spe
`cafic Stru urally spec ftc drugs which most dir gs arc
`act at spec ific sites
`such as
`rcceptor or an nzymc Iherr act vaty
`tency
`ad
`ble to small cha ages In chemica strucU rc
`kculc
`tivatas tcnd to havc comr on structural
`no spcc tic satc
`action
`ay occur witf
`baoboga al ctivities
`anesthetics sedati
`
`no
`
`it
`
`roputi
`ik quater
`Irom ies
`tud
`fund on
`
`atcd hat abc
`
`ic
`
`fib
`
`ha of
`
`di
`
`faa
`
`drugs arc asecu
`aid di nfcctuat
`
`cry susdepti
`amilar hio ogacal
`Stru wn
`ro rs eq/I
`fcaturcs
`havc ba ci potc
`malar
`Exampi
`uctur
`tot cs nd rarity
`
`id ssu
`ty of
`va
`ad
`
`of thcs
`
`ala eptics
`
`ti
`
`at
`
`cit
`
`hr
`
`souatcd
`
`ath at
`
`oFcuk
`on
`thougt
`achy
`part
`okcula irodilic tions that could be
`aty their arc multiud cf
`adc
`ny
`SAR mdi
`th yn
`inpl mvolv
`1960s
`escs of
`th
`prior
`ny
`analogs as pos iWe of he Icad and thei
`to dct
`tIc effc
`of
`ity or po cncy Oncc cnou It
`str tcturc on acta
`ado
`pa cd and
`re
`saithcicrat data acc imul ted conclusions could It madc raardan sun tuic
`activity relationships
`An excellent cx4rnple of this approach carte from the dcvdopment of
`the
`numt cr of analogs of
`sulfonamide antibacterial agents sulfa drugs After
`the lead compound sullanilamick 2.1
`wcre prepared at was found
`that compounds of this general structure exhibited diuretic and antidiabetic
`activities as well as antimicrobial activity Compounds with each tye of
`activity eventually were shown to possess cntaiu structural teiture an com
`mon On the hais of the biological results of greater than 10 000 compound
`scveral SAR gencrahzations have been made
`ntnmcrohr ri agents have
`SO NHR or SO
`structure 229
`where
`the amin
`tn
`sulfonyl
`roups on thc benzcne rang should bc para
`thc anihno amino group may hr
`rcrnoved ir wo
`unsubstatutr.d as shown or may hav
`substitucnt
`that
`the hcntcnc ring by othr.r rang syatr.ms or thr introduction of
`rcphaceinr.nt ot
`
`NH
`
`29
`
`

`
`Drug Deveopment
`
`Lead Mod hcahon
`
`15
`
`additional cubstituents on it decreases the potency or abohshes the activity
`may be
`
`SO2
`
`NH2 SO
`
`NH2 NI2 NHR or
`
`but
`Nmonosubstttutaon
`the potency is reduced in most cases
`SO2NHR results in more potent compounds and the potency increases wiTh
`SO NR
`heteroaro natic substitution and
`in gen
`disubstitutron
`eral leads to inactive compounds
`Antidiabetic agents are compounds with structure 2.30 where may be
`or
`incorporated into heteroaromatic structure such as
`thiadiazole or
`urea or thioura In the case of
`pyrimidine or in an acyclic structure such as
`ureas the N2 should carry as
`two carbon
`subtituent
`chain of at
`least
`atoms 20
`
`SON
`
`30
`
`two general
`typrs Ii diochio
`Sulfonamide diuretics are of
`structural
`rothiazides 2.31 and the high ceiling type 2.32 The former compounds
`have
`is an clectronega
`disulfamyl groups on the benzene ring and
`five group such as Cl Cl3 or NHR
`he high ceiling compounds contain
`is Cl Ph or Phi where may
`carboxy groups Suhstitucnt
`suit unyl
`or NH and
`and is nor naliy NHR
`be
`can be at position
`or
`OR or SR
`Fhc sulfonamide example is strong evidenec
`th
`notion that
`to support
`correlation does exist between structure and activity but how do you know
`what molecular modifications to mike in order
`to fine tune the bad corn
`pound
`
`o2
`
`NHSO2
`
`oo
`
`231
`
`NHSO2
`
`CO
`
`232
`
`Structure Modifications to Increase Potency and Therapeutic
`
`Index
`
`In the preceding scetion it was made clear that structure modifications were
`the keys to activity and potency manipulations After years of structure
`activity relationship studies various standard molecular modification ap
`
`

`
`18
`
`DrLIg Discovery Design and Devopment
`
`proaches have been developed for the systematic improvement of the thera
`peutzc index also called the therapaaic ratio which is measure of the ratio
`ofiindcirabJe to desirable drug effects For in UIVu systems the therapeutic
`the LD the lethal dose for 50% of the test
`index could be the ratio of
`animals to the ED0 the effective dose that produces the maximum therapeu
`in 50% of the test animals The largcr the therapeutic index the
`tic effect
`greater the margin of safety of the compound
`number of these structural
`modification methodologies follow
`
`Hotnoogatkrn
`
`group of compounds that differ by ntant unit
`hurau1ugoi erie is
`H2 group As will become more apparent in Section IIE biologi
`generally
`cal properties of homologous compounds show regularities of increase and
`decrease For many series of compounds lengthening of
`saturated carbon
`side chain from one methyl to five to rune atoms pentyl to nonyl produces
`sudden
`an increase in pharmacological effects further lengthening results in
`decrease in potency Fig LI In Section IIF2b it will be shown that this
`phenomenon corresponds to increased hpophihcity of the molecule which
`permits penetration into cell membranes until
`its lowered watet solubility
`hcomcs prublematie in aa tranpurt thruugh dqucuu mcdid In th Cnc uf
`at about
`aliphatic amrncs another problem is micclk formation which begin
`This effectivly removes the compound from potential
`interaction with
`the appropriate receptors One of if not the earliest example of this potency
`versus chain length phenomenon was reported by Richardson8 who was
`
`10
`
`11
`
`Chain Length
`
`Figure 21 Genera effect of carbon chain ength on drug potency
`
`

`
`Drug Deveopment
`
`Lead Modficatior
`
`17
`
`on Potency Antbacterab Actvdy of
`Table 21 Eftact of dhaln Length
`4-nAlkyresorcrno1s and Spasmolyhc Activtty of Mandeate EstOb
`
`o1
`
`oft
`
`cuo
`
`Phenol coeffk ent
`
`Spaurolync activity
`
`metyt
`
`cthy
`
`abutyl
`
`apeiii
`
`pL4
`
`mdc
`
`opi
`
`bin
`
`anyt
`
`22
`
`Si
`
`30
`
`27
`
`07
`
`08
`
`28
`
`30
`
`90
`
`22
`
`09
`
`85
`
`28
`
`Relatwe to 335 tnmethyeyclohexano set at 100%
`
`investigating the hypnotic activity of tlcohols ftc maximum eftcct occurrcd
`thcn th potency dcchned upon chain Iengthcnmg
`hcxanol to
`octanol
`fot
`until no activity was observed for hexadecanol
`study by Dohme el aLl2a on
`alkyl substituted resorcinol derivatives
`showed that the peak antibacterial activity occurred with
`hexvlresorcinol
`compound now used as
`see Table 2.1
`vanety of
`topical anesthetic
`in
`throat lozenges Funcke ci al 22b found that the peak spasinolytic activity of
`nonyl ester see T%ble 2.1
`series of mandelate esters occurred with the
`
`

`
`18
`
`ug Discovery Design aid Deveopmert
`
`Chain Brandiing
`
`is
`
`When
`sin plc hpophilic rclationship is irr portant as described above thcn
`chain brarchin lowers the potency of
`compound This phenomenon
`exemplified by tlc lower potency of the compounds having isoalkyl chms in
`Chain branching also yin interfere with receptor binding For cx
`able
`ample phenethylamine Ph HC NH is an excellent substrate for mono
`oxidase flavin contammg but
`amine oxidase
`rnethy1phencthyl
`poor substrate Pnmary amines often arc more
`amine amphetamine is
`than secondary ammcs which arc more potent
`than tertiary amines
`potent
`For example the intimalariaJ drug primaquine 233 is much more potent
`than its secondary or tertiary amine homologs
`Major pharmrcological changes can occur with chain branching and homol
`When
`onsider the 10 aminoalkyiphenothiazines 2.34
`ogation
`CH H3N
`promethazine or CH2CHNCH3 diethazinc anti
`spasmodic and antihistaminic activities predominate However
`the homolog
`being CH CH CII2NC1132 piomaiine has greatly reduced anti
`2.34 with
`spasmodic and antihistaminic activities but sedative and tranquilizing activi
`ties are greatly enhanced
`In the case of the branched chain analog 2.34 with
`to CH2CH H3CII2NCH32 trimeprazine the tranquilizing activity is
`equal
`reduced and antipruritic anti
`itch activity increases
`
`is
`
`H3O
`
`NFI HCH
`
`33
`
`234
`
`Ring Chain Transforniation
`
`Another modification that can be made is the transformation of AIkyl sub sti
`tu nts into cyclic analogs onsidcr the promazines again 2.34 Chlorprorna
`H2CH2NCH3J
`Cl
`Cl
`and 2.34
`line
`
`CH2CH2CH
`
`Tnmc.prazine
`line
`
`are
`
`equivalent
`
`as
`
`tranquilizers in
`
`animal
`
`tests
`
`CH2CHCH3CH2NCH32
`H2
`
`and methdila
`
`have similar antipruritic activity
`
`H3
`
`H2
`man
`
`

`
`Drug Devopment
`
`Lead Modiffcaton
`
`19
`
`Diffcrent activities can result from ring chain transformation as well For
`the dimethylamino group of chiorpromazine is substituted by
`example if
`
`merhylpiperatlue ring 234
`
`ii
`
`UH2CHICHN\
`
`JNCHJ proW
`
`nausea and vomiting activity is
`chloiperanne the antiemetic prevents
`greatly enhanced In this case however an additional amino group is added
`
`Bioisostedsxn
`
`Bioisostere are substituents or groups that have chemical or physical sunilar
`ities and which produce broadly similar biological properties2 Bioisostensm
`lead modification approach that has been shown to be useful to atenuate
`is
`lead and it may have
`toxicity or to modify the activity of
`significant role in
`the alteration of metabolism of
`lead There are classical
`isosteres242 and
`In 1925 Grimm2 formulated the hydride displace
`nonelassical
`isosteres
`law to describe similarities between groups that have the same number
`meni
`of valence electrons but may have
`different number of atoms 1rlenmneyer28
`later redefined isosteres as atoms ions or molecules in which the peripheral
`layers of electrons can be considered to be identical These two definitions
`describe classical Lostere examples are shown in Table 22 Nonclassical
`
`Table 22 Class cal sosteres
`
`Urnvaknt atuma and groups
`CH NH OH
`CI
`bCI
`PH
`SH
`Br Pr
`dl
`IOu
`Biv lent
`turns and groupe
`CH
`NH
`OC
`CONHR
`ores and groups
`
`rivalent
`
`CII
`
`As
`
`etravaknt
`
`turns
`
`COR
`
`05k
`
`Ring equwalcnts
`CII CII
`CH
`
`eg naerp tluophene
`berzcne pynthrie
`CH
`NH
`
`Ce
`
`tetrahydrofuran
`
`tetrahvdrotl
`
`tophene
`cyclopentane pyrrolidine
`
`

`
`Tabe23
`
`ste
`
`E7
`
`dl
`
`Nt
`
`dm
`
`NN
`
`Nd
`
`Pp
`
`Mpdrp
`
`Nt
`
`NE
`
`

`
`Drug Devc1opmet Lead Modif ation
`
`21
`
`do not havc the same number of atoms and do not fit
`bwzo3ter
`and electronic rules of the classical
`isosteres but they do produec
`in biological activity Examples of these are shown in Table
`Ruig chain tI4rIsfoLmatun iO can be considcicd tu bc iwttric inter
`changes There are hundreds of examples of compounds that differ by
`some examples are shown in Table
`Bioisos
`bioisosteric interchange2326
`the sulfw atom of
`terismn also can
`lead to changes
`If
`in activity
`phenothiaiine neuroleptic drugs 234 is replaced by the
`bioisosteres then dibenzazepine antidepressant drugs 235
`Cli CH2
`result
`
`the steric
`
`similarity
`
`the
`
`or
`
`235
`
`It
`
`is actually quite surprising that bmoisosterism should be such
`success
`ful approach to lead modification Perusal of Table 22 and especially of Table
`makes it clear that in making
`biolsosteric replacement one or more of
`the following parameters will change size shape electronic distribution
`lipid solubilLty water solubihty pK chenucal
`reactivity and hydiogen
`to thc it uf aCtiun thc motciact with it
`drug mut gvt
`bundmg Bccaue
`modifications made to molecule may have one or more of
`see Chapter
`the following effects
`
`Structural
`
`If
`
`replaced by
`
`biomsostere has
`
`structural
`
`then size
`
`If
`
`If
`
`the moiety that
`role in holding other functionalities in
`particular geometry
`shape and hydrogen bonding will he Important
`the moiety replaced is involved in
`interactions
`Receptor
`specific
`interaction with
`receptor or enlyrre then all of the parameters except
`lipid and water solubdity will be important
`harmacokinetmcs
`for absorption
`the moiety replaced is necessary
`transport and excretion collectively with metabolism termed pharma
`eokinrucm of the compound then lipophilicity hydrophihcity pK and
`hydrogen bonding will be irnpoi Cant
`Metabolism if
`the moiety replaced is involved in blocking or aiding
`metabolism then the chemical meactivic will be import itt
`
`It
`
`is
`
`ecause of these subtle changes that hmorsosterism is effective
`this
`approach allows the medicinal chemist to tinker with only some of he param
`zfl urder to ugmnt the poten ckctimty
`tti
`and lurator
`actioi and
`to reduce toxicity Multiple alterations may be necessary
`to counterbalance
`involved in binding
`or example if modification of
`effects
`functionality
`also decreases the lipophiheity of the molecule thereby reducing its ab lity to
`
`

`
`Table 24
`
`xar etB os si
`
`ri
`
`%al
`
`Neurokph
`
`tantpsyn9h
`
`coy
`
`dDeveoprrert
`
`Anti nflarnmtory agents
`
`H3
`
`UI
`
`Ktha
`
`NiH
`
`SN
`
`ilv
`
`AntUiistamiues
`
`NHOCH2
`
`

`
`Drug Deveopment
`
`Lead Modthcation
`
`23
`
`penetrate cdl walls and cross other membranes the molecule can be substi
`tuted with additional bpophihc groups at sites distant from that involved with
`binding Modifications of this sort may change the overall naolccular
`shape
`and rcsult
`in another activity
`Up to this point we have been discussing more or lcss random molecular
`lead in 1868 Crum Brown
`modifications to make qualitative diffuences in
`relationship betwen
`and Jraser predicted that some day mathematical
`structure and activity would be expressed It was not until almost 100 years
`new era in drug design was
`this prediction began to be realized and
`later that
`born In 1962 orwin Hansch attempted to quantify the effects of particular
`substituent modifications and from this quantitative structure activity rd
`tionship QSAR studies dcv e1oped
`
`Quantitative StructureActivity Relationships
`
`Historicat
`
`The concept of quantitative drug design is based on the fact that th bioIogieaI
`function of its ptythoehemkal paratneteri
`compound are
`properties of
`thai is physical properties such as solubility Ilpophilicimy electronic effects
`profound influence on the chem
`ionization and stereochemistry that Ii
`ive
`istry of the compounds The first attempt to relate
`physicochemical pararne
`He observed
`pharmacological effect was
`sported in 1893 by Richet
`tel to
`the narcotic action of group of orginic compounds was inversely related
`that
`to their water solubility Jrehets rule Overton
`and Meyer32 related tadpole
`narcosis induced by
`series of nonioniied compounds added to the water hi
`which the
`idpoles were swimming to the