`
`The Grgfanre Chemistry of
`Drug Design and Drug Action
`
`Richard B. Silverman
`
`Department of Chemistry
`Northwestern University
`Evanston, Illinois
`
`ACADEMIC PRESS, INC.
`A Division ofHarcourt Brace & Company
`San Diego New York Boston London Sydney Tokyo Toronto
`
`SAWAI EX. 1016
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`Page ’I of 8
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`SAWAI EX. 1016
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`This book is printed on acid-flee paper.
`
`Copyright © 1992 by ACADEMIC PRESS, INC.
`All Rights Reserved.
`No part of this publication may be reproduced or transmitted in any form or by any
`means, electronic or mechanical, including photocopy, recording, or any information
`storage and retrieval system, without permission in writing from Ihe'publisher.
`
`Academic Press, Inc.
`A Division ofHarcourt Brace & Company
`525 B Street, Suite 1900, San Diego, California 921014495
`United Kingdom Edition published by
`Academic Press Limited
`24—28 Oval Road, London NW1 7DX
`
`Library of Congress Cataloging—in—Publication Data
`
`Silver-man, Richard B.
`The organic chemistry of drug design and drug action /Richard B.
`Silverman.
`p.
`cm.
`Includes index.
`ISBN 0— 1 26437300 (hardcover)
`1. Pharmaceutical chemistry.
`2. Bioorganic chemistry.
`3. Molecular pharmacology.
`4. Drugs-Design.
`I. Title.
`[DNLM: 1. Chemistry, Organic.
`2. Chemistry, Pharmaceutical.
`3. Drug Design. 4. Pharmacokinetics. QV 744 S5870]
`123403.855
`1992
`615'.19--dc20
`.
`' DNLM/DLC
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`for Library of Congress
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`91-47041
`CLP
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`PRINTED 1N THE UNITED STATES OF AMERICA
`959697 MM 9876543
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`SAWAI EX. 1016
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`Different activities can result from a ring—chain transformation as well. For
`example, if the dimethylamino group of chlorpromazine is substituted by a
`
`/
`.
`.
`.
`methylplperazme ring (2.34, X = C1, R = CHZCHZCHZN
`
`\
`NCH3; pro~
`
`the antiemetic (prevents nausea and vomiting) activity is
`chlorperazine),
`greatly enhanced. In this case, however, an additional amino group is added.
`
`4. Bioisosterism
`
`Bioisosteres are substituents or groupsthathave chemical or physical similar—
`ities, and Which produce broadly sirnilar 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 isosteres“ZS and
`nonclassical isosteres};26 In 1925 Grimm27 formulated the hydride displace-
`ment law to describe similarities between 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 which the peripheral
`layers of electrons can be considered to be identical. These two definitions
`describe classical isosteres; examples are shown in Table 2.2. Nonclassical
`
`Table 2.2 Classical lsos’teresz“-25
`
`.
`
`1. Univalent atoms and groups
`a. CH; NH; OH F C1
`b. Cl
`PH;
`SH
`c. Br
`i—Pr
`d. I
`t-Bu
`2. Bivalent atoms and groups
`——S—
`—O——
`a. ———CH1—
`—NH—-
`b. —-COCH2R —CQNHR ~—C02R —COSR .
`3. Trivalent atoms and groups
`5
`a. ——CH=
`—-N==
`b. ——P=
`~As=
`4. Tetravalent atoms
`
`——Se—-—
`
`a. All-
`
`will.
`
`+
`= =
`
`+
`=P=
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`Il. Drug Development: Lead Modification
`19
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`
`
`b. =C=
`5. Ring equivalents
`a. —~CH=CH— —S—
`b. —CH=
`...u. =
`c. ~0—
`
`
`(e.g., benzene, thiophene)
`
`(e.g., benzene, pyridine)
`
`——CH2— —-NH— (6.g. , tetrahydrofuran,
`
`tetrahydrothiophene,
`
`cyclopentane, pyrrolidine)
`
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`SAWAI EX. 1016
`Page 3 of 8
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`Table 2.3 Nonclassical Bioisosteres23
`
`l.
`
`Carbonyl group
`
`
`
`u
`/5\
`
`0‘10
`)5;
`
`CN
`I
`--CH--
`
`O
`u
`’— 5~0H
`g
`
`O
`u
`~‘ P—OH
`N 1
`
`0
`n
`~" Pg—‘OH
`DE:
`
`0
`n
`-"C--NH
`C"
`
`O.
`
`N
`
`CH
`
`OH
`
`O
`
`0
`
`N'N
`/ u
`N
`
`H
`
`Hydroxy group
`O
`H
`-NHCR —-NHso,R
`
`O
`H
`——CH,0H ——NHCNH,
`
`-—NHCN
`Culechol
`
`—cmcmx
`
`H
`\
`”’13 an ”36
`H0
`N
`HO \ x
`X=D.NR
`
`\-
`°
`Ho'N ’
`
`2.
`
`3.
`
`4.
`
`5.
`
`Halogen
`
`cs,
`
`CN mm), mm),
`
`
`
`
`1
`\
`
`1
`
`C"
`NC CN
`/o\ X /N\
`
`.CN
`)1
`
`NH:
`
`—NH
`
`N01
`
`""2
`
`i
`
`—NH
`
`6.
`
`74
`
`8.
`
`9.
`
`Thioelher
`
`
`Tyinuren
`
`5
`AHJJ‘NHI
`Azomelhlne
`
`CN.
`
`EEI ~c=
`Pyridine
`
`0
`"I
`
`No;
`
`~
`(3
`E"
`R
`
`+
`NR,
`
`10.
`
`Spacer gronp
`
`[©—
`Hydrogen
`
`ll;
`
`
`
`E] F
`
`i i
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`< EE
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`I‘
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`5
`t
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`ii. Drug Development: Lead Modification
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`21
`
`bioisosteres do not have the same number of atoms and do not fit the steric
`and electronic rules of the classical isosteres, but they do produce a similarity
`in biological activity. Examples of these are shown in Table 2.3.
`Ring—chain transformations also can be considered to be isosteric inter~
`changes. There are hundreds of examples of compounds that differ by a
`bioisosteric interchange23v26; some examples are shown in Table 2.4. Bioisos-
`terism also can lead to changes in activity. If the sulfur atom of the
`phenothiazine neuroleptic drugs (2.34) is replaced by the -—CH=CH——- or
`WCHZCHZ—~ bioisosteres, then dibenzazepine antidepressant drugs (2.35)
`result.
`
`
`
`2.35
`
`It is, actually, quite surprising that bioisosterism should be such a success-
`ful approach to lead modification. Perusal of Table 2.2, and especially of Table
`2.3, makes it clear that in making a bioisosteric replacement, one or more of
`the following parameters will change: size, shape, electronic distribution,
`lipid solubility, water solubility, pKa, chemical reactivity, and hydrogen
`bonding. Because a drug must get to the site of action, then interact with it
`(see Chapter 3), modifications made to a molecule may have one or more of
`the following effects:
`1. Structural. Ifthe moiety that is replaced by a bioisostere has a structural
`role in holding other functionalities in a particular geometry, then size,
`shape, and hydrogen bonding will be important.
`2. Receptor interactions. If the moiety replaced is involved in a specific
`interaction with a receptor or enzyme, then all of the parameters except
`lipid and water solubility will be important.
`3. Pharmacokinetics. If the moiety replaced is necessary for absorption,
`transport, and excretion (collectively, with metabolism, termed pharma-
`cokinetics) of the compound, then lipophilicity, hydrophilicity, pKa, and
`hydrogen bonding will be important.
`4. Metabolism. If the moiety replaced is involved in blocking or aiding
`metabolism, then the chemical reactivity will be important.
`
`It is because of these subtle changes that bioisosterism is efiective. This
`approach allows the medicinal chemist to tinker with only some of the param-
`eters in order to augment the potency, selectivity, and duration of action and
`to reduce toxicity. Multiple alterations may be necessary to counterbalance
`effects. For example, if modification of a functionality involved in binding
`also decreases the lipophilicity of the molecule, thereby reducing its ability to
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`22
`
`2. Drug Discovery, Design, and Development
`
`
`Table 2.4 Examples of Bioisosteric Analogsfla-zfi
`
`1.
`
`Neuroleptics
`
`(antipsycnotics)
`
`
`
`R
`/C\
`
`X:
`
`or CHCN
`
`N
`
`\
`
`NH
`
`2.
`
`Anti-inflammatory agents
`
`x = OH (indomethacin)
`
`==NHOH
`N‘N
`/
`‘1‘?N‘
`H
`
`=
`
`Y=CH3d Z=Ci
`
`Y=F
`
`2 = SCH3 (suh'ndac)
`
`X
`
`0
`CH3
`
`OH
`
`0
`
`\
`N
`A
`o
`
`o‘
`
`CH30
`
`Cl
`
`Y
`
`Z
`
`3.
`
`Antihistamines
`
`R—-X——(CH7),,——Y
`
`X=NH,0,CH2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`:
`
`
`Y = N<CH3)2
`
`(n = 2)
`
`1)
`
`J3 m
`.
`
`NH
`
`
`
`
`
`H N
`
`._
`/N/)(n —1,2)
`
`
`
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`Ii. Drug Development: Lead Modification
`
`23
`
`penetrate cell walls and cross other membranes, the molecule can be substi-
`tuted with additional lipophilic groups at sites distant from that involved with
`binding. Modifications of this sort may change the overall molecular shape
`and result in another activity.
`Up to this point We have been discussing more or less random molecular
`modificatibns to make qualitative differences in a lead. In 1868 Crum-Brown
`and Fraser” predicted that some day a mathematical relationship between
`structure and activity would be expressed. It was not until almost 100 years
`later that this prediction began to be realized and a new era in drug design was
`born. In 1962 Corwin Hansch attempted to quantify the effects of particular
`substituent modifications, and from this quantitative structure—activity rela—
`tionship (QSAR) studies developed.29
`
`E. Quantitative Structure-Activity Relationships
`
`1. Historical
`
`The concept of quantitative drug design is based on the fact that the biological
`properties of a compound are a function of its physicochemical parameters,
`that is, physical properties, such as solubility, lipophilicity, electronic effects,
`ionization, and stereochemistry, that have a profound influence on the chem-
`istry of the compounds. The first attempt to relate a physicochemical parame-
`ter to a pharmacological effect was reported in 1893 by Richet.3° He observed
`that the narcotic action of a group of organic compounds was inversely related
`to their water solubility (Richet’s rule). Overton31 and Meyer32 related tadpole
`narcosis induced by a series of nonionized compounds added to the water in
`which the tadpoles were swimming to the ability of the compounds to parti-
`tion between oil and water. These early observations regarding the depressant
`action of structurally nonspecific drugs were rationalized by Ferguson.33 He
`reasoned that, for a state of equilibrium, simple thermodynamic principles
`could be applied to drug activities, and that the important parameter for
`correlation of narcotic activities was the relative saturation (termed thermo-
`dynamic activity by Ferguson)" of the drug in the external phase or extracellu-
`lar fluids. This is known as Ferguson’s principle, which is useful for the
`classification of the general mode of action of a drug and for predicting the
`degree of its biological effect. The numerical range of the thermodynamic
`activity for structurally nonspecific drugs is 0.01 to 1.0, indicating that they
`are active only at relatively high concentrations. Structurally specific drugs
`have thermodynamic activities considerably less than 0.01 and normally be—
`low 0.001.
`In 1951 Hansch et al.34 noted a correlation between the plant growth activ—
`ity of phenoxyacetic acid derivatives and the electron density at the ortho
`position (lower electron density gave increased activity). They made an at-
`
`
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`SAWAI EX. 1016
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`2. Drug Discovery, Design, and Development
`
`References
`
`,s
`lii
`
`Eiaa l!
`
`42.
`
`43.
`44.
`45.
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`Hansch, C., and Leo, A. 1979. “S
`and Biology.” Wiley, New York.
`Leo, A., Hansch, C., and Elkins
`Iwasa, J ., Fujita, T., and Hansch
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`Bodor, N., Gabanyi, Z., and W0:
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`Seiler, P. 1974. Eur. J. Med. Che
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`Verloop, A., Hoogenstraaten, W
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`Free, S'. M., Jr., and Wilson, J. Vi
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`Fried, J. and Barman, A. 1958. V
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`23.
`24.
`25.
`
`26.
`27.
`28.
`29.
`30.
`31.
`32.
`33.
`34.
`35.
`36.
`
`37.
`38.
`39.
`40.
`41.
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`SAWAI EX. 1016
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