The Organic Chemistry of
`Drug Design and Drug
`Action, 1992, Pages 4-51
`CHAPTER 2
`Richard B. Silverman
`Drug Discovery, Design,
`and Development
`
`5
`
`t 1
`
`I. Drug Discovery
`4
`A. Drug Discovery without a Lead
`l. Penicillins, 5 • 2. Librium, 6
`8. Lead Discovery
`7
`1. Random Screening, 8 • 2. Nonrandom Screening, 9 • 3. Drug ~ietabolism Studies,
`9 • 4. Clinical Observations, 9 • 5. Rational Approaches to Lead Discovery, 10
`II. Drug Development: Lead Modification
`11
`A. Identification of the Active Part: The Pharmacophore
`13
`B. Functional Group Modification
`C. Structure-Activity Relationships
`14
`15
`D. Structure Modifications to Increase Potency and Therapeutic Index
`I. Homologation, 16 • 2. Chain Branching, 18 • 3. Ring-Chain Transformations, 18 •
`4. Bioisosterism, 19
`23
`E. Quantitative Structure-Activity Relationships
`l. Historical, 23 • 2. Physicochemical Parameters, 24 • 3. 1iethods Used to Correlate
`Physicochemical Parameters with Biological Activity, 35 • 4. Computer·Based
`1'fethods of QSAR Related to Receptor Binding, 43
`F. hfolecular 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 kno\vn 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 activities, insolubility, or 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
`
`Breckenridge Exhibit 1015
`Breckenridge v. Novartis AG
`
`

`
`I. Drug Discovery
`
`A. Drug Discovery without a Lead
`1. Penicillins
`
`5
`
`In 1928 Alexander Fleming noticed a green mold growing in a culture of
`Staphylococcus 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 that this observation was made by other scientists
`who just ignored it, and, therefore, Fleming was unique for following up on it.
`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 of unlikely events all took place simultaneously. Hare found
`that very special conditions were required to produce the phenomenon ini(cid:173)
`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 refrigerator or incubator when he went on
`vacation as is normally done, Fleming inadvertently left it on his lab bench.
`When he returned the following month, he noticed the lysed bacteria. Ordi(cid:173)
`narily, penicillin does not lyse these bacteria; it prevents them from develop(cid:173)
`ing, but it has no effect if added after the bacteria have developed. However,
`while Fleming was on vacation (July to August) the weather was unseason(cid:173)
`ably cold, and this provided the particular temperature required for the mold
`and the staphylococci to grow slowly and produce the lysis. Another extraor(cid:173)
`dinary circumstance was that the particular strain of the mold on Fleming's
`culture was a relatively good penicillin producer, although most strains of that
`mold (Penicillium) produce 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 systemically.' but the full extent of the value of penicillin was
`not reveaJed 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 II. The pharmacology, production, and clinical application of
`penicillin were not revealed until after the war so that this wonder drug would
`
`H2N-o-S02NHR
`
`2.1
`
`

`
`6
`
`2. Drug Discovery, Design, and Development
`
`not be used by the Germans. A team of Allied scientists who were interrogat(cid:173)
`ing German scientists involved in chemotherapeutic research were told that
`the Germans thought the initial report of penicillin was made just for commer(cid:173)
`cial reasons to compete with the sulfa drugs. They did not take the report
`seriously.
`The original mold was Pe11icillii11n 11otatun1, a strain that gave a relatively
`lO\V yield of penicillin. It was replaced by Penicilliuni chrysogenutn,6 \Vhich
`had been cultured from a mold gro\ving on a grapefruit in a market in Peoria,
`Illinois! The correct structure of penicillin (2.2) was elucidated in 1943 by Sir
`Robert Robinson (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 = PhOCH,, penicillin V, and 2.2, R = CH,Ph, penicillin G) are still in use
`today.
`
`2. Librium
`The first benzodiazepine tranquilizer drug, Librium [7-chloro-2-(methyl(cid:173)
`amino)-5-phenyl-3H-l,4-benzodiazepine 4-oxide, 2.3], was discovered seren(cid:173)
`dipitously.' Dr. Leo Stembach 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 R1 was CH2NR2 and R2 was C,,H5 , it
`was found that the actual structure was that of a quinazoline 3-oxide (2.5).
`Ho\vever, 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-CI, R' = CH2NHCH,, R2 =
`C,,H5) 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 screening of tranquilizers.
`
`N'=)NHCH3
`
`Cl
`
`N+
`""-Q
`
`I
`
`"'
`2.3
`
`2.4
`
`f.i(NY.R1
`x-JvyN~0-
`
`Y
`
`R'
`2.5
`
`

`
`I. Drug Discovery
`
`7
`
`Cl
`
`2.6
`
`Scheme 2.1. Mechanism for formation of Librium.
`Further investigation revealed that the compound was not a quinazoline
`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-oxide (2.6) with methylamine (Scheme 2.1). If this compound had not
`been found in the laboratory cleanup, all of 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 have been discovered for man-y
`years to come.
`The examples of drug discovery without a lead are quite few in number.
`The typical occurrence is that a lead compound is identified and its structure
`is modified to give, eventually, the drug that goes to the clinic.
`
`B. Lead Discovery
`
`Penicillin V and Librium are, indeed, hvo 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
`elucidation of the earliest penicillins. Valium (diazepam, 2.7) was synthesized
`at Roche even before Librium 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.
`
`

`
`8
`
`2. Drug Discovery, Design, and Development
`
`2.7
`
`In general, the difficulty arises 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 approaches is to have a means to assay compounds
`for a particular biological activity, so that it will be known when a compound
`is active. A bioassay (or screen) is a means of determining in a biological
`system, relative to a control compound, whether a compound has the desired
`activity and, if so, what the relative potency of the compound is. Note the
`distinction between the terms activity and potency. Activity is the particular
`biological or pharmacological effect (e.g., antibacterial activity or anticon(cid:173)
`vulsant activity); potency is the strength of that effect. Some bioassays (or
`screens) begin as in vitro tests, for example, the inhibition of an enzyme or
`antagonism of a receptor; others are in vivo tests, for example, the ability of
`the compound to prevent an induced seizure in a mouse. In 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.
`
`1. Random Screening
`Random screening involves no intellectualization; all compounds 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 classes 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 was screened in a mouse tumor bioassay. Few ne\v
`anticancer drugs resulted from that screen, but many kno\Vn anticancer drugs
`also did not show activity in the screen used. As a result of that observation,
`multiple bioassay systems are now utilized. In the 1940s and 1950s a random
`screen by various pharmaceutical companies of soil samples in search of new
`antibiotics was undertaken. In this case, ho\vever, not only \Vere numerous
`leads uncovered, but two important antibiotics, streptomycin and the tetracy(cid:173)
`clines, were found.
`
`

`
`I. Drug Discovery
`
`2. Nonrandom Screening
`
`9
`
`Nonrandom screening is a slightly more narrow approach than is random
`screening. In this case compounds having a vague resemblance to weakly
`active compounds uncovered in a random screen or compounds 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 tumor screens, as it was
`realized that cancer is not just a single disease.
`
`3. Drug Metabolism Studies
`
`During metabolism studies drug metabolites (drug degradation products gen(cid:173)
`erated in vivo) that are isolated are screened in order to determine if the
`activity observed is derived from the drug candidate or from a metabolite. For
`example, the anti-inflammatory drug sulindac (2.8) is not the active agent; the
`metabolic reduction product, 2.9, is responsible for the activity.' A classic
`example of this approach is the discovery of the antibacterial agent sulfanil(cid:173)
`amide (2.1, R = H), which was found to be a metabolite of prontosil (2.10)
`(see Chapter 5, Section IV,B,l for details).
`
`NH2
`NH,-0--N=N-O-so,NH,
`
`2.10
`
`4. Clinical Observations
`Often a drug candidate during animal testing or clinical trials will exhibit more
`than one pharmacological activity; that is, it may produce a side effect. This
`compound, then, can be used as a lead for the secondary activity. In 1947 an
`antihistamine, dimenhydrinate (2.11; Dramamine") was tested at the allergy
`clinic at Johns Hopkins University and was found also to be effective in
`
`

`
`10
`
`2. Drug Discovery, Design, and Development
`
`relieving a patient who suffered from car sickness; a further study proved its
`effectiveness in the treatment of seasickness9 and airsickness. 10 It is now the
`most widely used drug for the treatment of all forms of motion sickness.
`An antibacterial agent, carbutamide (2.12, R = NH2), was found to have an
`antidiabetic side effect. Ho,vever, it could not be used as an antidiabetic drug
`because of its antibacterial activity. Carbutamide, then, was a lead for the
`discovery of tolbutamide (2.12, R = CH3), an antidiabetic drug without anti(cid:173)
`bacterial activity.
`
`-0-
`
`R
`
`0
`II
`sol'-~HCNHCH2CH2CH2CH3
`
`2.12
`
`5. Rational Approaches to Lead Discovery
`
`None of the above approaches to lead discovery involves a major rational
`component. The lead is just found by screening techniques, as a by-product of
`drug metabolism studies, or from \Vhole 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 the cause for the disease state. Most diseases, or at least the
`symptoms of diseases, arise from an imbalance of particular chemicals in the
`body, from the invasion of a foreign organism, or from aberrant cell growth.
`As discussed in later chapters, the effects of the imbalance can be corrected
`by antagonism or agonism of a receptor (see Chapter 3) or by inhibition of a
`particular enzyme (see Chapter 5). Foreign organism enzyme inhibition and
`interference with DNA biosynthesis or function (see Chapter 6) are also im(cid:173)
`portant approaches to treat diseases arising from microorganisms and aber(cid:173)
`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 17a-ethynylestra(cid:173)
`diol (2.14) were the steroidal hormones progesterone (2.15) and l7{:l-estradiol
`
`0
`
`2.13
`
`HO
`
`2.14
`
`

`
`II. Drug Development: Lead Modification
`
`11
`
`(2.16). Whereas the steroid hormones 2.15 and 2.16 show weak and short·
`lasting effects, the oral contraceptives 2.13 and 2.14 exert strong progesta(cid:173)
`tional activity of long duration.
`
`0
`
`CH,
`
`OH
`
`CH,
`
`H
`
`0
`
`2.15
`
`HO
`
`2.16
`
`At Merck it was believed that serotonin (2.17) was a possible mediator of
`inflammation. Consequently, serotonin \Vas used as a lead for anti-inflamma(cid:173)
`tory agents, and from this lead the anti-inflammatory drug indomethacin (2.18)
`was developed. 11
`
`HO~NH,
`V-1
`
`H
`2.17
`
`OH
`
`'"' I
`"--
`
`'\ en,
`N
`
`CH3o~o
`I ff o
`
`Cl
`
`I
`
`2.18
`
`The rational approaches are directed at lead discovery. It is not possible,
`\Vith much accuracy, to foreteH toxicity and side effects, anticipate transport
`characteristics, ot predict the metabolic fate of a drug. Once a lead is identi(cid:173)
`fied, 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 kno\V \vhat to modify in
`order to improve the desired pharmacological properties?
`
`A. Identification of the Active Part: The Pharmacophore
`
`Interactions of drugs \Vith receptors are very specific (see Chapter 3). There(cid:173)
`fore, only a small ~art of the lead compound may be involved in the appropri(cid:173)
`
`ate interactions. T re relevant groups on a molecule that interact with a recep-
`
`

`
`12
`
`2. Drug Disoovel)', Design, and Development
`
`tor and are responsible for the activity are collectively known as the
`pharmacophore. If the lead compound has additional groups, they may inter(cid:173)
`fere with the appropriate interactions. One approach to lead modification is to
`cut a\vay sections of the molecule in order to determine what parts are essen(cid:173)
`tial and which are superfluous.
`As an example of ho\v a molecule can be trimmed and still result in in(cid:173)
`creased potency or modified activity, consider the addictive analgetics mor(cid:173)
`phine (2.19, R = R' = H), codeine (2.19, R = CH,, R' = H), and heroin
`(R = R' = COCH3 ). The pharmacophore is darkened, If the dihydrofuran
`oxygen is excised, morphinan (2.20, R = H) 12 results; the hydroxy analog
`levorphanol" (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 of the cyclo(cid:173)
`hexene ring, leaving only methyl substituents, gives benzomorphan (2.21,
`R = CH3)," This compound shows some separation of analgetic and addic(cid:173)
`tive effects; cyclazocine (2,21, R = CH,-<J) and pentazocine [2.21, R =
`CH2CH=C(CH3) 2] are analogs with much lower addiction liabilities. Cutting
`away the cyclohexane fused ring (2.22) 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% of the
`overall potency of morphine. 15 Even acyclic analogs are active. Dextropro(cid:173)
`poxyphene (2.24, Darvon®) is one-half to two-thirds as potent as codeine; its
`activity can be ascribed to the fact that it can assume a conformation related
`to that of the morphine pharmacophore. Another acyclic analog is methadone
`(2,25) which is as potent an analgetic as morphine; the (-)-isomer is used in
`the treatment of opioid abstinence syndromes in heroin abusers.
`
`C\H3
`
`R
`I
`
`C\H3
`
`'\,H3
`
`OR
`
`2.19
`
`~·· ~ ~"" 6:
`
`I: OH
`
`OH
`
`2.20
`
`H3
`
`OH
`
`"
`
`/,
`
`2.21
`
`OH
`
`2.22
`
`CH3
`
`2.23
`
`2.24
`
`2.25
`
`

`
`II. Drug Development: Lead Modification
`
`13
`
`In some cases an increase in structural complexity and/or rigidity can lead
`to increased potency. For example, an oripavine derivative such as etorphine
`(2.26, R = CH3 , R' = C3H7), which has a two-carbon bridge and a substituent
`not in morphine, is about 1000 times more potent than morphine 16 and, there(cid:173)
`fore, is used in veterinary medicine to immobilize large animals. The related
`analog, buprenorphine (2.26, R = CH2-<J, 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, the additional rigidity of the oripavine de(cid:173)
`rivatives increases the appropriate receptor interactions (see Chapter 3).
`Once the pharmacophore is identified, manipulation of functional groups
`becomes consequential.
`
`OH
`
`2.26
`
`B. Functional Group Modification
`
`The importance of functional group modification was seen in Section l,B,4;
`the amino group of carbutamide (2.U, R = NH2) was replaced by a methyl
`group to give tolbutamide (2.U, R = CH3), and in so doing the antibacterial
`activity was separated away from the antidiabetic activity. In some cases an
`experienced medicinal chemist knows what functional group will elicit a par(cid:173)
`ticular effect. Chlorothiazide (2.27) is an antihypertensive agent that has a
`strong diuretic (increased urine excretion) effect as well. It was known from
`sulfanilamide work that the sulfonamide side chain can give diuretic activity
`(see Section II,C). Consequently, diazoxide (2.28) was prepared as an antihy(cid:173)
`pertensive drug \Vithout 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.
`
`2.27
`
`2.28
`
`

`
`14
`
`2. Drug Discovery, Design, and Development
`
`C. Structure-Activity Relationships
`
`In 1868 Crum-Brown and Fraser, 17 suspecting that the quaternary ammonium
`character of curare may be responsible for its muscular paralytic properties,
`examined the neuromuscular blocking effects of a variety of simple quater(cid:173)
`nary ammonium salts and quatemized alkaloids in animals. From these stud(cid:173)
`ies 1hey concluded 1ha11he physiological action of a molecule was a function
`of its chemical constitution. Shortly thereafter, Richardson" noted that the
`hypnotic activity of aliphatic alcohols was a function of their molecular
`weight. These observations are the basis for future structure-activity relation(cid:173)
`ships (SAR).
`Drugs can be classified as being structurally specific or structurally nonspe(cid:173)
`cific. Structurally specific drugs, \vhich most drugs are, act at specific 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 potency. Similar
`biological activities may occur with a variety of structures. Examples of these
`drugs are gaseous anesthetics, sedatives and hypnotics, and many antiseptics
`and disinfectants.
`Even though only a part of the molecule may be associated with the activ(cid:173)
`ity, there are a multitude of molecular modifications that could be made. Early
`SAR studies (prior to the 1960s) simply involved the syntheses of as many
`analogs as possible of the lead and their testing to determine the effect of
`structure on activity (or potency). Once enough analogs were prepared and
`sufficient data accumulated, conclusions could be made regarding structure(cid:173)
`activity relationships.
`An excellent example of this approach came from the development of the
`sulfonamide antibacterial agents (sulfa drugs). After a number of analogs of
`the lead compound sulfanilamide (2.1, R = H) were prepared, it was found·
`that compounds of this general structure exhibited diuretic and antidiabetic
`activities as well as antimicrobial activity. Compounds with each type of
`activity eventually \Vere shown to possess certain structural features in com(cid:173)
`mon. On the basis of the biological results of greater than 10,000 compounds,
`several SAR generalizations have been made. 19 Antimicrobial agents have
`structure 2.29 (R = S02NHR' or S03H) where (I) the amino and suifonyi
`groups on the benzene ring should be para; (2) the anilino amino group may be
`unsubstituted (as shown) or may have a substituent that is removed in vivo; (3)
`replacement of the benzene ring by other ring systems, or the introduction of
`
`NH2-o-R
`
`2.29
`
`

`
`II. Drug Development: Lead Modification
`
`15
`
`additional substituents on it, decreases the potency or abolishes the activity;
`(4) R may be
`
`0
`
`0
`
`0
`
`S0, -0-NH,, so-0-NH,, ~NH,, ~NHR, or ~-o-R.
`but the potency is reduced in most cases; (5) N'-monosubstitution (R =
`SO,NHR') results in more potent compounds, and the potency increases with
`heteroaromatic substitution; and (6) N'-disubstitution (R = S01NR2), in gen(cid:173)
`eral, leads to inactive compounds.
`Antidiabetic agents are compounds \Vith structure 2.30, where X may be 0,
`S, or N incorporated into a heteroaromatic structure such as a thiadiazole or a
`pyrimidine or in an acyclic structure such as a urea or thiourea. In the case of
`ureas, the N 2 should carry as a substituent a chain of at least t\VO carbon
`atoms. 20
`
`R-0-'\ S01NHC-~
`a·
`-
`1:
`i
`........
`x~.
`
`2.30
`
`Sulfonamide diuretics are of two general structural types, hydrochlo(cid:173)
`rothiazides (2.31) and the high ceiling type (2,32). The former compounds
`have 1,3-disulfamyl 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
`1-sulfamyl-3-carboxy groups. Substituent R1 is Cl, Ph, or PhZ, where Z may
`be 0, S, CO, or NH, 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
`correlation does exist between structure and activity, but ho\v do you kno\v
`what molecular modifications to make in order to fine-tune the lead com(cid:173)
`pound?
`
`·y
`
`/
`RXX ' N. R'
`"' I
`NH
`~S,S
`0
`0
`
`NH2S02
`
`2.31
`
`2.32
`
`D. Structure Modifications to Increase Potency and Therapeutic Index
`
`In the preceding section it \Vas made clear that structure modifications \Vere
`the keys to activity and potency manipulations. After years of structure(cid:173)
`activity relationship studies, various standard molecular modification ap-
`
`

`
`16
`
`2. Drug Discovery, Design, and Developmenl
`
`proaches have been developed for the systematic improvement of the thera(cid:173)
`peutic index (also called the therapeutic ratio), which is a measure of the ratio
`of undesirable to desirable drug effects. For in vivo systems the therapeutic
`index could be the ratio of the LD5f! (the lethal dose for 50% of the test
`animals) to the ED50 (the effective dose that produces the maximum therapeu(cid:173)
`tic effect in 50% of the test animals). The larger the therapeutic index, the
`greater the margin 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,
`generally a CH2 group. As will become more apparent in Section 11,E, biologi(cid:173)
`cal properties of homologous compounds show regularities of increase and
`decrease. ·For many series of compounds, lengthening 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
`decrease in potency (Fig. 2.1). In Section 11,E,2,b it will be shown that this
`phenomenon corresponds to increased lipophilicity of the molecule, which
`permits penetration into cell membranes' until its lowered water solubility
`becomes problematic in its transport through aqueous media. In the case of
`aliphatic amines another problem is micelle formation, \Vhich 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 was
`
`I 2 3 4 5 6 7 8 9
`
`IO 11 12
`
`C Chain Length
`
`Figure 2.1. General effect of carbon chain length on drug potency.
`
`

`
`II. Drug Development: Leed Modification
`
`17
`
`Table 2.1 Effect of Chain Length on Potency: Antibacterial Activity of
`4-n-Alkylresorcinols22a and Spasmolytic Activity of Mandefate Esters22b
`
`OH
`
`Q-tttCOzR
`
`JI°"
`
`R
`
`/,
`
`OH
`
`R
`
`methyl
`
`e1hyl
`
`11-propyl
`
`11-butyl
`
`11-pentyl
`
`11-hexyl
`
`11-hcptyl
`
`11-octyl
`
`11-nonyl
`
`11-decyl
`
`11-unde.;yl
`
`i-propyl
`
`i-butyl
`
`i-amyl
`
`i-he.\yl
`
`Phenol coefficient
`
`% Spasmolytic activity"
`
`0.3
`
`0.7
`
`2.4
`
`9.8
`
`28
`
`"
`
`SI
`
`130
`
`190
`
`37
`
`22
`
`0.9
`
`8.3
`
`28
`
`22
`
`33
`
`SI
`
`30
`
`0
`
`0
`
`0
`
`0
`
`JS.2
`
`23.8
`
`27
`
`"Relative to 3,3,5-trimethylcyclohexanol, set at lOO°Ai.
`
`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 a1.v.a on 4-alkyl-substituted resorcinol derivatives
`showed that the peak antibacterial activity occurred with 4-11-hexylresorcinol
`(see Table 2.1), a compound no\v used as a topical anesthetic in a variety of
`throat lozenges. Funcke et al. nb found that the peak spasmolytic activity of a
`series of mandelate esters occurred with the n·nonyl ester (see Table 2.1).
`
`

`
`18
`
`2. Chain Branching
`
`2. Drug Discovel)', Design, and Development
`
`When a simple lipophilic relationship is important as described above, then
`chain branching lo\vers the potency of a compound. This phenomenon is
`exemplified by the lower potency of the compounds having isoalkyl chains in
`Table 2.1. Chain branching also can interfere with receptor binding. For ex(cid:173)
`ample, phenethylamine (PhCH2CH2NH2) is an excellent substrate for mono(cid:173)
`amine oxidase [amine oxidase (flavin-containing)], but a-methylphenethyl(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 example, 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 10-aminoalkylphenothiazines (2.34, X ~ H). When R is
`CH2CH(CH3)N(CH3), (promethazine) or CH2CH2N(CH3), (diethazine), anti(cid:173)
`spasmodic and antihistarninic activities predominate. However, the homolog
`2.34 with R being CH2CH2CH2N(CH3), (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 of the branched chain analog 2.34 with R
`equal to CH2CH(CH3)CH2N(CH3), (trimeprazine), the tranquilizing activity is
`reduced and antipruritic (anti-itch) activity increases.
`
`CH3o~
`I "
`"
`-" N~
`
`NHfH(CH2)3NH2
`CH,
`
`2.33
`
`cc:nx
`
`~
`2.34
`
`3, Ring-Chain Transformations
`
`Another modification that can be made is the transformation of alkyl substi(cid:173)
`tuents into cyclic analogs. Consider the promazines again (2.34). Chlorproma(cid:173)
`zine [2.34, X = Cl, R = CH2CH2CH2N(CH3),] and 2.34 (X = Cl, R =
`tranquilizers
`in animal
`tests.
`
`CH2CH2CH2N8 are equivalent as
`
`Trimeprazine [2.34, X ~ H, R = CH2CH(CH3)CH2N(CH3),] and methdila·
`zine [2.34, X = H, R ~ CH2-CH-CH1
`I
`)N-CH,]
`bH,-CH2
`have similar antipruritic activity in man.
`
`

`
`II. Drug Development: Lead Modification
`
`19
`
`Different activities can result from a ring-chain transformation as \Vell. For
`example, if the dimethylamino group of chlorpromazine is substituted by a
`I \
`methylpiperazine ring (2.34, X = Cl, R = CH2CH2CH2N\__;NCH3 ; pro-
`
`chlorperazine), the antiemetic (prevents nausea and vomiting) activity is
`greatly enhanced. In this case, however, an additional amino group is added.
`
`4. Bioisosterism
`
`Bioisosteres are substituents or groups that have chemical or physical similar(cid:173)
`ities, and \Vhich produce broadly similar biological properties.23 Bioisosterism
`is a lead modification approach that has been shown to be useful to attenuate
`toxicity or to modify the activity of a lead, and it may have a significant role in
`the alteration of metabolism of a lead. There are classical isosteres24•25 and
`nonclassical isosteres. 23•26 In 1925 Grimm27 formulated the hydride disp/ace-
`111e11t /a1v to describe similarities bet\veen groups that have the Same number
`of valence electrons but may have a different number of atoms. Erlenmeyer28
`later redefined isosteres as atoms, ions, or molecules in \Vhich the peripheral
`layers of electrons can be considered to be identical. These two definitions
`describe classical isosteres; examples are sho\vn in Table 2.2. No11classical
`
`Table 2.2 Classical lsosteres24.2'5
`
`I. Univalent atoms and groups
`a. CH 3 NH2 OH F Cl
`PH2 SH
`b. Cl
`c. Br
`i-Pr
`d. I
`t-Bu
`2. Bivalent atoms and groups
`a. -CH:r-
`-0-
`-NH-
`b. -COCH2R
`-CONHR -C01R
`3. Trivalent atoms and groups
`a. -CH=
`-N=
`b. -P=
`-As=
`4. Tetravalent atoms
`
`-S-
`-COSR
`
`-Se-
`
`a.-t-
`
`1
`
`b. ~c~
`5. Ring equivalents
`a. -CH=CH-
`b. -CH~
`c. -0-
`
`-~i­
`i
`+
`
`~N~
`
`-s-
`-N~
`-s-
`
`(e.g., benzene, thiophene)
`(e.g., benzene, pyridine)
`-CH:r- -NH- (e.g., tetrahydrofuran,
`tetrahydrothiophene,
`cyclopentane, pyrrolidine)
`
`

`
`Table 2.3 Nonclasslcal Blolsosteresn
`
`L
`
`cu•u7l &•HP
`
`[I]
`
`'
`
`R
`/i1~r-
`o,
`
`l'C~
`;<,
`
`R
`,•,
`
`';s~
`
`0
`II
`-rn-
`I
`
`I"
`-rn-
`
`'·
`
`'
`
`•
`
`'
`..
`
`'·
`
`..
`..
`
`"·
`, ..
`
`C.rl>olJlic add iroup
`
`[Q
`-c-r1
`R
`rn
`
`R
`R
`0
`"
`-~-yu -S-Oil -~-OH
`I
`II
`'"•
`0
`0
`•
`
`-~-Ofi
`I
`~
`
`(Jz
`
`00
`
`&°" ---1.!.""1!,
`)/'
`'
`
`HJdr<>lf &•HP
`
`8
`
`0
`II
`-1'11C'k
`
`-1'l!C'I
`
`ft
`-:.mo,r; ~'°" -h'ltC'<"l!•
`-ca.on,
`
`Cat<ckol
`
`~ '
`(:0
`'
`
`HllGltl
`
`0 a, C< SlO), UC.'l,
`
`):) 0
`HO'n
`
`x~o."1.
`
`T•toellter
`
`0
`
`Tltlnru
`
`'°'
`
`1 _,.A,~. I
`
`"X'
`
`p
`,•,
`
`~
`
`' )l
`
`~'ll NH,
`
`j""
`
`1'111
`
`---l<.11
`
`Ato..,tlltlu
`p
`
`1~=1
`
`-C::OO:
`
`l'Jrldlu
`
`[Q] Q (J Q
`i·
`""
`s,.~ .. ,, ... ,
`1--(CH,>,-l -0-
`
`m,
`
`H7dn1u
`
`®
`
`'
`
`

`
`II. Drug Development: Lead Modificalion
`
`21
`
`bio