/
`
`'
`
`The Organic Chemis · of
`Drug Design ,and Drug Action,/
`
`"-,;,1
`
`Richard B.,,SHverman
`Department of Chemistry
`Northwestern University
`Evanston1 Illinois
`
`ACADEMIC PRESS
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`Silvcmmn, Richard a.
`The organic ch¢mistry of drug design and dn1& attion I Richard B.
`Silverman.
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`lrtcliideS ifti,1e~.
`ISBN 0.!2-643730.0{ha{ooover)
`l .• :Pharmattmtical chemistr,y~ 2 .. Bioorganic chemjstry.
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`I. '11lle~
`{DNLM:. L Chemistry, ~t\ 2. Chemistry, Ptunmru:eulical.
`3. Drug Des'J:gn. 4. Phtumacokinetics~ QV 744 S587oJ
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`

`
`CHAPTER 2
`Dru,g Discovery, Design,
`and Development
`
`5
`
`11
`
`4
`l. Drug Discovery
`A. Drug Discovery Witlnmt a Lead
`L PeniciUins, 5 • ?. Librium, 6
`B. Lead Discovery
`7
`.1. Random Screening, 8 • 2. Nonrandom Screening, 9 • 3. Drug Metabolism Studies,
`9 • 4. Clinical Observations, 9 • 5 ... Rational Approaches io Lead Discovery, to
`lL Drug Development: Lead Modification
`11
`A. Identification of the Active Part: 'The Pharmacophor.e
`It Funciiomtl Group Modification
`13
`14
`C. Structure-Activity Relationships
`.D. Structure Modifications to Increase Potency and Therapeutic Index
`15
`1. Homologation, J6 • 2. Chain Bt~nching. rn • 3 . .Ring-Chain Transtbrmatfons, 18 •
`4. Bioisosterism, 19
`·
`.
`E. Quatltitative Structure-Activity Relationships
`23
`L Historical, 23 • 2. Physicochemical Parameters, 24 • 3. Methods Used to Correlate
`iPbysicochemical Parameters with BlologlcaJ Activity, 35 • 4. Computer-Base•i
`Methods of QSAR Related to Receptor Binding, 43
`F. Molecular Graphics-Based Drug Design
`44
`G. '.Epilogue
`47
`References
`47
`General References
`
`50
`
`I. Drug Discovery
`
`In general, clinically used drugs are not discovered. What is more likely
`discovered is known as a lead compound. The lead is a prototype compound
`that has the desired biological or pharmacological activity, but may have
`many other undesirable characteristics, for example, high toxicity, other bio(cid:173)
`logical activitie.s. insolubility. ot metabolism problems. The structure of the
`lead compound is then modified by synthesis to amplify the desired activity
`and to minimize or eliminate the unwanted properties. Prior to an elaboration
`of approaches to lead discovery and lead modification, two of the rare drugs
`discovered without a lead are discussed.
`
`4
`
`

`
`f. Drug Discovery
`
`A. Drug Discovery without a_ Lead
`l. Penicillins
`
`5
`
`In 1928 Alexander Fleming noticed a green mold growing in a culture of
`Staphylo(:occus aureus, and where the two had converged, the bacteria were
`lysed. 1 This led to the discovery of penicillin, which was produced by the
`mold. It may be thought th.at this observation was made by other scientists
`who just ignored it, and, therefore, Fleming was unique for following up onit.
`However, this is not the case. Fleming tried many times to rediscover this
`phenomenon without success; it was his colleague, Dr. Ronald Hare,2•3 who
`was able to reproduce the observation. It only occurred the :first time because
`a combination ~funlikely events all took place simultaneously. Hare found
`that very spcciru conditions were required to produce the phenome11on ini(cid:173)
`tially observed by Fleming. The cmtlire dish inoculated by Fleming must have
`become accidentally and simultaneously contaminated with the mold spore.
`Instead of placing the dish in the refrigerator or incubator when he went on
`vacationas is normally done~ Fleming inadvertently left it ort bis lab bench.
`When he returned the following month, he noticed the lysed bacteria. Ordi~
`narily, penicillin does 11ot lyse ·these bacteria; it prevents 1hell1 from develop~
`ing, but it has nci effect if added after the bacteria have developed. However,
`while Fleming was 011 vacation (July fo August) the weather was uns~son­
`ably cold, and this provided the particular temperature requited for the mold
`and the staphylococci to grow slowly and produce the lysis. Another extraor(cid:173)
`dinary circumstance was that the particular strain ofthe mold on Flellling's
`culture was a relatively good penicillin producer, although ID()St strains of that
`mold (Penicillium)pro<lµce no penicillin at all. The mold presumably came
`from the laboratory just below Fleming,s where research on molds was going
`on at the time.
`Although Fleming suggested that penicillin could be useful as a topical
`antiseptic, he was not successful in producing penicillin in a form suitable to
`treat infections. Nothing more was done until Sir Howard Florey at Oxford
`University reinvestigated the possibility of producing penicillin in a useful
`form. In 1940 he succeeded in producing penicillin that could be administered
`topically and systcniically.4 but the full extent of the value of penicillin WdS
`not revealed until the late 1940s.5 Two reasons for the delay in the universal
`utilization of penicillin were the emergence of the sulfonamide antibacterials
`(sulfa drugs, 2.1; see Chapter 5, Section IV ,B, l) in 1935 and the outbreak of
`World War IL The pharmacology, production, and clinical application of
`penicillin were notrevealed until after. the war so that this wonder drug would
`
`H2N-O\_S02NHR
`
`2.1
`
`

`
`2. Drug Discovery, Design, and Development
`
`not be used by the Germam.. A team of i\Hied scientists who were interrogat(cid:173)
`ing German scientists involved in chernotherapcmk: research were told that
`the Germans thought the initial report of penicillin \VM made just for comme:r(cid:173)
`cfal reasons to compete whh the sulfa drugs. They did nol take the report
`seriously.
`The t)riginal rn(>ld was Penicillium notmum, a strain that gave a relatively
`low yield of penicillin. It was replaced by Penicilliwn chrysogenum/' which
`had been cultured from a mold growing on a grapefruit in a market in Peoria,
`Ulinois ! The correct structure of penidllin (2.2) was elucidated in l 943 by Sir
`Robert Robiilson (Oxford) and Karl Folkers (Merck). Several different peni(cid:173)
`cillin analogs (R group varied) were isolated early on: only two of these (2.2,
`R = PhOCH2 , penicillin V, and 2.2, R = CHiPh, penicillin G) are still in use
`today.
`
`2. Librium
`
`The first benzodiazepine tranquilizer drug, Librium f7·chlorn~2-(methyl­
`atnino)-:5-phenyl-3H-l ,4-benzodiazepine 4-oxide, 2.3J, was discovered seren(cid:173)
`dipitously .7 Dr. Leo Stembacb at Roche was involved in a program to synthe(cid:173)
`size a new class of tranquilizer drugs, He originally set out to prepare a series
`of benzheptoxdiazines (2.4), but when R 1 was CH2NR2 and R2 was CeH5 , it
`was found that the actual structure was that of a q.uinazoline 3-oxide (2.5).
`Howeveri none of these compounds gave any interesting pharmacological
`results. The program was abandoned in 1955 in order for Sternbach to work
`on. a different project. In 1957 during a general laboratory cleanup a vial
`containing what was thought to be 2.5 (X = 7-CJ, R 1 = CH2NHCH3 , R2 =
`CoH5) was found and, as a last effort, was submitted for pharmacological
`testing. Unlike all the other compounds submitted) this one gave very promis(cid:173)
`ing results in six different tests used for preliminary :screenfrig of tranquilizers.
`
`NHCH3
`f~0J("' N~
`,.....::.._, 6N+
`I
`i
`
`l
`• ·, _
`0
`
`Cl
`
`~!
`~'
`2.3
`
`2.4
`
`2.5
`
`

`
`l. Drug Discovery
`
`7
`
`2.6
`
`Scheme 2.1. Mechanism for formation of Ubrlum.
`
`Further investigation revealed that the compound was not a qninazoline
`3-oxide but, rather, was the benzodiazepine 4-oxide (2.3), presumably pro(cid:173)
`duced in an unexpected reaction of the corresponding chloromethyl quinazo(cid:173)
`line 3-ox.ide (2.6) with methylamine (Scheme 2.1). ff this compound had not
`been found in the laboratory cleanup; all Qf the negative pharmacological
`results would have been reported for the quinazoline 3-oxide class of com(cid:173)
`pounds~ and benzodiazepine 4-oxides may not bave been discovered for many
`years to come.
`The examples of drug discovery without a lead are quite few in number.
`The typical occurrence is that a lead compt)1,md is identified a.nd its structure
`is modified to give, eventually. the drug that .goes to the clinic.
`
`B. Lead Discovery
`
`Penicillin V and Librium are, indeed, two important drugs that were discov(cid:173)
`ered without a lead, Once they were identified, however, they then became
`lead compounds for future analogs. There are now a myriad of penicillin(cid:173)
`derived antibacterials that have been synthesized as the result of the structure
`eiucidation of the earliest penicillirts. Valium (diazepam, 2.7) was synthesized
`at Roche even before Ubrium was introduced on to the market; this drug was
`derived from the lead compound Librium and is almost 10 times more potent
`than the lead.
`
`

`
`2,7
`
`In general. the difficulty alises in the discovery of the lead compound.
`There are several approaches that can be taken to identify a lead. The first
`requirement for all of the appmaches is to have a means to assay compounds
`for ii partfoofar biological activity, SO that it Will be known \Vhen a CO.mjiOUtld
`is active. A bioassay (or screen) is a means of determining in a biological
`systenh relative to a control compound~ -whether a compound has the desi.red
`activity and, if so, -"vhat d1e relative potency of the compound is. Note the
`distin°ction between the terms activity and poteney . . 4c:tivity is the particular
`bfofogie.,qf or pharmarofogical effect (e.g., antibacterial .activity or antkon(cid:173)
`vttlsant activity)~ potency is the :strength of loot effect. Some bioassays (or
`screens) begfa as i11 vitro tests, for exruuple, the inhibition of an enzyme or
`antagonism of a receptor; others are in vivo tests. fiJr example, the ability of
`the compound to prevent an induced seizure in a mouse. ln general. the in
`vitro tests are quicker and less expensive. Once the bioassay .is developed,
`there are a variety of approaches to identify a lead.
`
`l. Raudom Screening
`Random screening involves no intetJectuatization; all cnrnpounds are tested in
`the bioassay without regard to their structures. Prior to 1935 (the discovery of
`sulfa drugs), random screening was essentially the only approach; today this
`method is used tO a lesser degree. However, random screening programs are
`still very important in order to discover drugs or leads that have unexpected
`and unusual structures for various targets.
`The two major dasses of materials screened are synthetic chemicals and
`natural products (microbial, plant, and marine), An example of a random
`screen of synthetic and natural compounds is the "war on cancer" declared
`by Congress and the National Cancer Institute in the early 1970s. Any new
`compound submitted wa:s screened. in a mouse tumor bioassay. _Few I}ew
`.anticancer drugs resulted from that screen, but many known anticancer rlrngs
`also 4kt not shuw activity in the screen ,used. As a result of that observation,
`~mi!fople hioassay systems are now utilized. In the 1940s and 1950s a random
`screen by various pharmaceutical companies of soil s~unples in search of new
`antibiotics was undertaken. In this case, however. not only were numerous
`leads uncovered, but two important antibiotics} '!llreptomycin and the letracy(cid:173)
`clines. were found.
`
`

`
`L Drug. Discovery
`
`2. Nonrandom Screening
`
`9
`
`Nonrandom screening is a slightly more narrow approach tha.rt is random
`screening. In this case compounds having a vagueresemblance to weakly
`active COmpOUnds UncOVeted in a random screen or COIDPOU!ldS containing
`different functional groups than leads may be tested selectively. By the late
`1970s the National Cancer Institute's random screen was modified to a non(cid:173)
`random screen because of budgetary and manpower restrictions. Also, the
`single tumor screen was changed to a variety of t1.1mor screens, as it w.as
`realized that cance:r is_p_o~ju~t a single.disease.
`..
`
`,-~·~-----·· ~
`
`~·
`
`.
`
`3. Drug· Metabolism. Studies
`During metabolism stuidies drug metabolites (drug degradation products gen(cid:173)
`erated in vivo). that ate faofated are screened in order to . determine if the
`a~tivity of)servedis-derive<lfromthedrugca!)didRrte orfrorn a.metabolite, F'or
`exainple. tfie anti".iuflammatory drug sulinc!ac(2..8) i$ not the active agent; the
`1llet$.bolic rnduction product, 2.9, is. r~sponsible fQr the activity, 8 A classic
`exruµple of this approa<::h is the di~covery of the antibacterial agent sulftmil(cid:173)
`amide (2.:J., R = H), which was found to be a. metabolite of prontosil (2.10)
`(see :Ghapter5, Sectkm IV ,B, 1 for details).
`'
`
`FmCOOH
`)
`s 0
`
`F
`
`2.8
`
`.....-:;'.
`
`CH3
`
`I
`CH3
`
`2 .. 9
`
`NH:,
`
`NI{i--<j-;::N~o-S02NR2
`
`2.10
`
`4. Clinical· Observations
`
`Often a drug candidate during animal testing or clinical trials will exhibit more
`than one pharmacologicaLactivity; thatis~ it may produce a side effect. This
`compound, then, can be ~sed <is afoad for the secondary acti.vity. In 1947 an
`antihistamine, dimenhydrinate (2.11; Dramamine®) was tested at the allergy
`clinic at Johns Hopkins University and was found also to be effecti.ve in
`
`

`
`10
`
`2. Drug Discovery, Design, ;;md Development
`
`relieving a patient who suffered from car sickness; a further study proved its
`effectiveness in the treatment of seasickness!' and airsickness. 10 It is now the
`most widely used drug for the treatment of .ciJl forms of motion sickness.
`An antibacterial agent, carbutamide (2.12, R = NH:2 ), w::ts found to have an
`anti.dia.1.:)efi~ side effect. However, it could not be used as an antidiabetic drug
`1)ecause of its ;<intibacteriaJ activity. Carbutamide, ~hen, was a Jead for the
`discovery of tdlbutamide (2.12, R = CH3), an antidiabetic drug without anti(cid:173)
`bacterial activity.
`
`-0-
`
`R
`
`0
`Jl
`so NHCNHCH CHACH CH
`.. 2 . ..
`.
`..
`1 .•. 2
`3
`
`5. Rafio:nal Approaches to Lead Discovery
`None of the above approaches to lead discovery involves a major rational
`component. The lead is just found bysc:reeningtechniques, as a by-product of
`drugmetabolism studies, or from whole animal investigations. Is it possible to
`design a compound having a particular activity? Rational approaches to drug
`design have now become the major routes to lead discovery. The first step is
`to identify th~ cause for the disease state. Most diseases, or at least the
`symptoms ofdiseases, arise from an imbalance of.particular chemicals in the
`body, frpp;t tbejnvasion of a fqreign organism, orfron:i aberrant cell growth.
`A:s(Jis<;li~sedin later chapters, the effects of the imbal=wce cap be corrected
`by ant._ligonis:O, or agonism of a receptor (see Chapter 3) or by inhibition of a
`pafficqlfir ~JJ.ZYJ}l~ (see Chapter 5). F'oreign organism enzyme inhibition and
`interference with DNA biosynthesis or function (see Chapter 6) are also im(cid:173)
`pprtant approa,cbes to treat .diseases arising from microorganisms and aber(cid:173)
`rant celtgrowth.
`Once the relevant biochemical. system is identified, lead compounds then
`become the natural receptor agonists {ff enzyme substrates. For example, lead
`compoundsforthe contraceptives ( +)~norgestrel (2.13) and l7a~ethynylestra­
`diol {2;14) were the steroidal hormones progesterone (2.15) and 17 /3-estradiol
`
`I
`
`I
`
`2.13
`
`2.14
`
`HO
`
`

`
`IL Drug Oevalopment: Lead Modlficaiioh
`
`(2.16) ... Whereas. the stem.id ·hormones 2.15 and 2.16 show weak and short(cid:173)
`lasting effects, the oral contraceptives 2.13 andi 2.14 exert strong progesta(cid:173)
`tional activity oflong duration.
`
`HO
`
`2.15
`2.16
`At Merck it was believed that serotonin (2.17) was a possible mediator of
`in.fuinutjation; Consequently, serotonin was us~ as a lead for anti-inflamma(cid:173)
`tory agents, and from this lead the anti-inflammatory drugindomethacin (2.18)
`was developed. 11
`
`HO m NH,
`
`;::.._,
`
`~
`N
`H
`2.17
`
`The rational approaches are dirncted at lead d.iscovecy. It is not possible,
`with much accuracy, to foretell toxicity and side effects, anticipate transport
`characteristics, or predict the metabolic fate of a drug. Once ~ lead is identi(cid:173)
`fied, its structure can be modified. until an effective drtig is prepared.
`
`II. Drug Deve.lopmen1: Lead Modification
`
`Once your lead compound is in hand. how do you know wnat to modify in
`order to improve the desired pharmacological properties?
`
`A. Identification of the Active Part: The Pharmacophore
`
`Interactions of drugs with receptors are very specific (see Chapter 3). There(cid:173)
`fore, only a small part of the lead compound may be involved in the appropri(cid:173)
`ate interactions. The relevant groups on a molecule thatinteract with a recep~
`
`

`
`12
`
`2. Drug Discovery, Design, and Development
`
`tor and are responsible for the activity are collectively known as the
`pharmf.!91Rl1Q!!· If the lead compound has additional groups, they may inter~
`Ture \Vlth t.he appropriate interactions. One approach to lead modification is to
`cut away sections of the molecule in order to determine what parts are essen(cid:173)
`tial and which are superfluous.
`As an example of how a molecule can be trimmed and still result in fo,.
`creased potency or modified activity, consider the addictive analgetics mor~
`phine (2.19, R = R 1 = H); codeine (2.19, R = CH3 , R' =JI), and heroin
`(R = R' = COCH;). The pharinacophore is darkened. If the dihydrofuran
`oxygen is excised, morphinan (2.20, R = H) 12 results; the hydroxy analog
`lev-0rphano113 (2.20, R = OH) is 3 to 4 times more potent than morphine as an
`analgetic, but it retains the addictive properties. Removal of half ofthe cyclc·(cid:173)
`hexene ring, leaving only methyl substituents, gives benzomotphan (2.21,
`.R "'~ CH3). 14 This compound shows some separati<>n of analgetic and addic(cid:173)
`tive effects; cyclazocine (2.21, R = CHr-<J) and pentazocine [2.2l, R =
`CH2CH=C(CH3)z] are analogs \vith much lower addiction liabilities. Cutting
`away the cyclohexanc fused ring (Z.22) also has little effect on the analgetic
`activity in animal tests. Removal of all fused rings, for example, in the case of
`meperidine (2.23, Demerol'®), gives an analgetic still possessing 10-12% ofthe
`overall potency of morphine. 15 Even acyclic analogs are active. Dextropro(cid:173)
`poxyphene (2.24, Darvon®) is one-half to t\vo-thirds as potent as codeine; its
`activity can be ascribed to the fact that it can assume a conformatfon refated
`to that of the tnorphine pharmacophore. Another acyclic analog is xnethadone
`(2.25) which is as potent an analgctic as morphine; the ( - }-isomer is used in
`the treatment of QJ?J~t~*:,l~~Jinence syndrom:es. in heroin abusers.
`
`CH.
`
`\
`
`3
`
`CH
`\ 3
`
`R
`\
`
`f:\Hs
`
`~ ~ ~; ~ H~.
`
`DR1
`
`OR
`
`OH
`
`2.19
`
`2.20
`
`'-._;:
`
`OH
`
`2.21
`
`,.,/
`
`~
`
`,
`
`OH
`
`2.22
`
`2.23
`
`2.24
`
`2.25
`
`

`
`I.I. Drug Development: leaq Modification
`
`13
`
`In some cases an increase in stmctnral complexity and/or rigidity can le.ad
`H) increas~d potency. For example, an oripavine derivative such as etorphine
`(2.26, R = CHJ • R' = C3H1), which has a two-carbon bridge and a substituent
`not in morphine, is about 1000 times more potent than morpnine 16 and, there(cid:173)
`fore, is used in veterinary medicine to immobilize large animals. The related
`analog, buprenorphine (2.26, R = CHr-<] , R' = tert~Bu, double bond re(cid:173)
`duced) is 10-20 times more potent than morphine and has a very Low level of
`dependence liability. Apparently, tbe additional rigidity of the oripavine de(cid:173)
`rivatives increases the appropriate receptor inter3ctions {see Chapter 3),
`Once the pharmacophore is identified, manipulation of functional groups
`becomes consequential.
`
`2.26
`
`B. Functional Group Modification
`
`The importance of functional group modification was seen in Section 1.B.4;
`the amino group of carbutamide (2.12, R = NH2 ) was replaced by a methyl
`group to give tolbutamide (2.12, R = CH3 ), and in so doing the antibacterial
`activity was separated away from tbe antidiabetic activity. In some cases an
`experienced medicinal chemist knows what functiomll group will elicit a p-ar(cid:173)
`ticular effect. Chlorot11iaz-ide (2.27) is an antihypertensive agent that has a
`strong diuretic (increased urine excretion) effect as welt It was known from
`sulfanilamide work that the sidfonamide side chain can give diuretic activity
`(see Section II~C). Consequently, dfazoxide (2.28) was prepared as an a.ntihy(cid:173)
`pertensive drug without diuretic activity.
`There, obviously., is a relationship between the molecular structure of a
`compound and its activity. This phenomenon was first realized over 120 years
`ago,
`
`l
`:I
`I
`
`2.27
`
`

`
`14
`
`C. Stroctum-Activity Relationships
`
`In 1868 Cmm-Brownand Fmser, 17 suspecting that the quaternary ammonium
`.character of <;Ura.re may be responsible for its muscular paralytic propertiies,
`ex1filhined the neuromuscular blo<!king effects of a variety of simple quater~
`nary ammonium salts and quatemized alkaloids in animals. From these stud(cid:173)
`ies tl}cy concluded th~L!b~ physiologic:aJ action of a mo!ecwe wasaJunction
`of its }:herni<:;aj cqr1stitution. Shortly therea,fter, Richardson 1a noted that the
`hyp:notic.<:\£tivhy of'aliphat:ic alcohols was a function of their molecular
`weight. These observations are the basisforfuture structure~activity relation(cid:173)
`ships (SAR).
`Drugs.can hedassjfied as ~~iµg structurnUy specific or structurally nonspe(cid:173)
`cific. Structurally specUictl.rug}, Which most drugs arc, act at spedfic sites,
`such as a receptor or an enzyme. Their activity and potency are very .suscepti(cid:173)
`ble to small changes in chemical. structure~ molecules With similar biological
`activities tend to have common structural features, Structurally nonspecific
`drugs have no specific site of action and usually have lower i.>"'Otency. Similar
`biological activities may occurwitb a variety of structures. Examples ofthese
`drugs are gas"€:Q>Us anesthetics.~ sedatNes and hypnotics. and many antiseptics
`and disinfectants.
`Eycn though only a· part of the molecule may be associated with the activ(cid:173)
`ity, there arc a multitude of molectlla.r modifications that could be made. Early
`SAR studies (prior to the 19608) simply involved the syntheses ofas m~ny
`analogs as possible of the· lead zjl(l iheir .t~sting to. deformine the effec;t of
`structure on activity (or potency). Once enough analogs were prepared and
`st1ffic1ent. data accumulated~ conclusions could be made regarding structore(cid:173)
`activ-ity ·relationships ..
`An excellent example of tbis approach came from the development of the
`sulfonamide antibacterial agents (sulfa drµgs). After a number of analogs of
`U1e lead compound sulfanilamide (2.1, R ::::=- H) wiere prepared, it was found
`that compounds of this general structure exhibited diuretic and antidiaootic
`activities as we-ll as antimicrobial activity. Compounds with each type of
`activity eventually were $hown to possess ccrt~n structural featutes in com(cid:173)
`mon. On the basis of the bfofogical results ofgteater than 10.:000 compounds~
`several SAR generalizations have been made. 19 Antimicrobi<:lt agents have
`structure 2.29 (R =· S02NHR' or S01H) where (1) the amino and sulfonyJ
`groups on the t.;;enz.ene ring should be para; (2) the anilino amino grou,p may r;e
`unsubstituted (as shown) or maybave a substituent that is removed in vivo; (3)
`replacement of the benzene ring by other ring systems. or the introduction of
`NH2~R
`
`2.29
`
`

`
`IL Drug Development Lead Modification
`
`Hi
`
`additional substituents on it, decreases the potency or abolishes the activity~
`(4) R may be
`
`0
`0
`0
`so,-Q-NH,, so-Q-NH,, ~NH2, ~NHR, or ~-u-R
`but the potency is reduced in most cases; (5) N*~monosubstilution (R =
`S02NHR') results in more potent compounds, and the potency increases with
`heteroaromatic substitution; and (6) N'-disubstitution (R = S02NR2), in gen(cid:173)
`eral, leads to inactive compounds.
`Antidi~abetic agents are compounds with strncture2.30, where X may be 0,
`S, or N incorporated into a heteroaromatic structure such as a thiadiazole or :a
`pyrimidine odn an acyclic structure such as a urea or thiourea. In the case of
`meas, the NZ should carry as a substitue;nt a chain -0f at least two carbon
`atoms.W
`
`2.30
`
`Sultbnamide diuretics are of two general structural types, hydroch1o(cid:173)
`mthiazides (2.31) and the high ceiling type (2.32). The former compounds
`have I ,3-disulfumyl groups on the benzene ring, and R2 is an electronega(cid:173)
`tive group such as Cl, CF3 , or NHR. The high ceiling compounds contain
`l-sulfamyl-3-carboxy groups. Substituent R1 is Cl, Ph, or PhZ. where Z may
`be O. S 1 CO, or N.H1 and X can be at position 2 or 3 and is normally NHR,
`OR, or SR.11
`The sulfonamide example is strong evidence to support the notion that a
`<:orreJation does exist bet\veen structure and activity, but how do you know
`what molecular modifications to make in order to fine-tune the le-ad com(cid:173)
`pound?
`
`2.31
`
`D. Structure Modifications to Increase Potency and Therapeutic Index
`
`1n the preceding section it was made clear that structure modifications were
`the keys to activity and potency manipulations. After years of stmcture(cid:173)
`activity relationship studies, various standard molecular modification ap-
`
`

`
`16
`
`2. Drug Dtscovery, Design, and Development
`
`proaches have been developed for the systematic improvement of tbej[len1-
`peutif)!1dex (also called the therapeutic ratio), which is a measure of the rat1o
`·.Qui.i1g_~_~frf!bfoJ<L'9.esimbJe drug effe~ts. For in vivo sysi.enis the therapeutic
`index could be lhe ratio of the LD50 (the lethal dose for 50% of the test
`animals) to the EDso (the effective dose that produces the maximum therapeu·
`tic effect in 50% of the test animals). Ttl~J&g~x.the.therapeutic index, the
`gi-~!~r th~U:!l.ftrgin of safety of the compound. A number of these structural
`modification methodologies follow.
`
`.,
`
`1. Homologation
`
`A homologous series is a group of compounds that differ by a constant unit,
`generaUy a CH2 group. As will become more apparent in Section JI,E, biologi(cid:173)
`cal properties of homologous compounds show regularities of increase and
`decrease. ·For many se1ies of c-0mpoun<ls 1 Jengthen.ing of a saturated carbon
`side chain from one (methyl) to :five to nine atoms (pentyl to nonyl) produces
`an increase in pharmacological effects; further lengthening results in a sudden
`qecrease in potency (Fig. 2.1). ln Section U,E;2,b it will be shown that this
`phenomenon corresponds to increased lipopi)ilicity of the m-0lecule, which
`permits pene1ration into ceU membranes' until its lowered water solubility
`becomes problematic in its transport t.hrough aqueous media. ln the case of
`a.liphatfo amines another problem is miceHe formation. which begins at about
`C12. This effectively 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 Richardson, 18 who \Vas
`
`l
`
`2 3 4 5 6 7 8 9 10 11 12
`
`C Chain Length
`
`Figure 2.1. General effect of carbon chain length on drug potency.
`
`

`
`!I. Drug Osve!op1mmt: Lead Modification
`
`Table 2.1 Effect of Chaln length on Potency: Antibacterial Activity of
`4-n~Alkylreoorcinolsz;:-a and Spasmolytic Activity of Mandelate Ester~b
`
`Phenol coefficient
`
`22
`
`3.1
`
`51
`
`.30
`
`0
`
`0
`
`0
`
`0
`
`l'.'.i.:2
`
`R
`
`methyl
`
`ethyl
`
`i-prcpyl
`
`i-but)'I
`
`1-heiiyl
`
`0.7
`
`9.8
`
`35
`
`Sl
`
`130
`
`190
`
`37
`
`0.9
`
`3.3
`
`2B
`
`a Relative to 3,3~5-trimethyic:yclohl!.xanol, set at 100':?6.
`
`investigating the hypnotic activity of alcohols. The maximum effect occurred
`for 1-hexanol to 1-octanol; then the potency declined upon chain lengthening
`until no activity was observed for hexadecanol.
`A study by Dohme et af.22u on 4~alkyl-substituted resordnol derivatives
`showed.that the peak antibacterial activity occurred with 4-n-hexylresorcinol
`(see Table 2. l), a compound now used as a topical anesthetic in a v;ulety of
`throat lozenges. Funcke et af.2'1.b found that thcpeakspasmolytic activity ofa
`series of mandelate esters occurred with the n-nonyl ester(see Table 2.1).
`
`

`
`2. Drug Discovery, Design, and Development
`
`2. Chain Branching
`When a simple lipophilic relationship is important as described above, then
`chain branchin,t;: lowers the potency of a compound, This phenomenon is
`exemplified by the lower potency of the compounds having isoalkyl chains in
`Table 2. l. Chain branching also can interfere with receptor binding. For ex(cid:173)
`ample, phenethylamine (PhCH2CH1NH2) 1s an excellent substrate for mono(cid:173)
`amine oxidase [amine oxidase (ftavin-containing)], but a-methylphenethyi(cid:173)
`amine {amphetamine) is a poor substrate. Primary amines often are more
`potent than secondary amines which are more potent than tertiary amines .
`.For exampJe, the antimalarial drug primaquine (2.33) is much more potent
`than its secondary or tertiary amine homologs.
`Major pharmacological changes can occur with chain branching and homol(cid:173)
`ogation. Consider the. m~aminoalkylphenothiazines (2.34, X = H). When R is
`CH2CH(CH3JN(CH3):~ (prnmethazine) or CH2CH2N(CH3) 2 (diethazine), anti(cid:173)
`spasmodic and antihistaminic activities predominate. However, the homolog
`2.34 with R being CH2CH2CH2N(CH3) 2 (promazine) has greatly reduced anti(cid:173)
`spasmodic and antihistaminic activities, but sedative and tranquilizing activi(cid:173)
`ties are greatly enhanced. In the case ofihe branched chain analog2.34 with R
`equal to CH1CH(CH3)CH2N(CH3) 2 (trimeprazine), the tranquilizing activity is
`reduced and antipruritic (anti-itch) activity increases.
`
`CH>O~
`Y""'N~
`NHCH(CH .. hNJI,
`I
`. .
`,.
`CH;1
`2,33
`
`2.34
`
`3. Ring-Chain Transformations
`
`Another modification that can be made is the transformation of alkyl subsli(cid:173)
`tuents into cyclic analogs. Consider the promazines again (2.34). Chlorproma·
`zine [2.34, X =CI. R = CH2CH2CH2N(CH3h] and 2.34 (X =Cl, R =
`r--.
`CH2CH2CHiN0 are equivalent as
`
`tests.
`
`tranquilizers
`
`in animal
`
`Trimeprazine [2.34, X = H, R = CH2CH(CH3)CH2N(CH3) 2] and methdila(cid:173)
`zine [2.34, X = H, R = CH2-CH-C~
`/N-CH3J
`CH2-CH2
`have similar antipruritic activity in man.
`
`,:
`
`

`
`r
`
`It Drug Development: Lead Modification
`
`i9
`
`Different activities can result from a ring-chain transformation. as well. For
`example, if t.he dimethylamino group of chlorpromazine is substituted by a
`;--\
`methylpipera:zine ring (2.34) X = Cl, R ""' CH2CH2CH2N\__/NCH1 ; pro.-
`
`chlorperazine), the antiemetic (prevents nausea and vomiting) activity is
`greatly .enhanced. fa this case, however, an a<lditional amino group is added.
`
`4. Bfoisosterlsm
`
`Bioisosteres are substituents or groups that have chemical or physical similar(cid:173)
`ities, and which produce broadly similar biological properties, 23 Bioisosterism
`is a lead modification approach that has been shown w be useful to attenuate
`toxicity or to modify the activity of a lead 1 and it may have a significant role in
`the alteration of metabolism of a lead. Then!' are classical isosteresz4,:z5 .and
`nonclassical isosteres.23;26 In 1925 Grimm27 fonuulated the.hydride displace(cid:173)
`ment law to describe similarities between groups that have the same number
`of valence electrons but may have a different number of atoms. Erlenme:yer28
`later redefined isosteres.as atoms, ions, nr molecules in which the peripheral
`layers of electrons can be considered to be identical. These two definitions
`describe classical tsosteres; exrunple:s are shown in Table 2.2. Nonclassical
`
`---S-
`---COSR
`
`-Se·--
`
`1. Univalent J\toms a:nd groups
`a. CH3 NH2 Ott F Cl
`PH1 SH
`b. Cl
`c. Br
`i·Pr
`r-.Bu
`rl, .!
`2. Bivalent atvms and groups
`a, -CHr-
`-0-
`-NH-
`---CONHR --COiR
`b. -COCH1R
`3. Trivalent atoms and grou