`
`The Organic 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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`SAWAI EX. 1016
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` SSATaIeesOT Pe EEE Teata
`SSTLSSaaNPISERPTO
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`PRINTED IN THE UNITED STATES OF AMERICA
`
`95 96 97 MM 9876 5 4 3
`
`
`SAWAI EX. 1016
`Page 2 of 8
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`This bookis printed on acid-free paper.
`
`Copyright © 1992 by ACADEMIC PRESS, INC.
`All Rights Reserved.
`Nopart ofthis 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 the’publisher.
`
`Academic Press, Inc.
`A Division ofHarcourt Brace & Company
`525 B Street, Suite 1900, San Diego, California 92101-4495
`United Kingdom Edition published by
`Academic Press Limited
`24-28 Oval Road, London NW1 7DX
`
`Library of Congress Cataloging-in-Publication Data
`
`Silverman, Richard B.
`The organic chemistry of drug design and drug action / Richard B.
`Silverman.
`p.
`cm.
`Includes index.
`ISBN 0-12-643730-0 (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 S587o]
`RS403.555
`1992
`615'.19--de20
`" DNLM/DLC
`for Library of Congress
`
`.
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`,
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`91-47041
`cIp
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`I. Drug Development: Lead Modification
`19
`
`Different activities can result from a ring—chain transformation as well. For
`example, if the dimethylamino group of chlorpromazine is substituted by a
`
`
`
`
`
`
`/
`.
`:
`.
`methylpiperazine ring (2.34, K = Cl, R = CH,CH,CH.N
`
`\
`NCH; 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 groups that-have chemical or physical similar-
`ities, and which producebroadly similar biological properties.” 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 havea significant role in
`the alteration of metabolism of a lead. There are classical isosteres*4> and
`nonclassical isosteres.73-6 In 1925 Grimm?’ formulated the hydride displace-
`ment law to describe similarities between groups that have the same number
`of valence electrons but may have a different numberof atoms. Erlenmeyer”
`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 Isosteres?425
`
`'
`
`1. Univalent atoms and groups
`a. CH; NH, OH F Cl
`b. Cl
`PH,
`SH
`c. Br
`i-Pr
`dl
`t-Bu
`2. Bivalent atoms and groups
`—-Oo— —s— —Se—
`a, —-CH,—
`—~NH—
`b. —COCH,R —CONHR -—CO,.R
`-—-COSR .
`3. Trivalent atomsand groups
`.
`a. —CH=
`—N==
`b, —P=
`~~Aga
`4. Tetravalent atoms
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`SA\
`
`
`
`
`
`
`
`
`
`
`
`a ao
`
`~s—
`
`+
`soxN=
`
`+
`soxPa
`
`b. ==C==
`5. Ring equivalents
`a, —CH==CH— —S—
`b. —CH=
`—N=
`c. —O—
`—5—
`
`(e.g., benzene, thiophene)
`(e.g., benzene, pyridine)
`—CH,;- —NH— (e.g., tetrahydrofuran,
`tetrahydrothiophene,
`cyclopentane, pyrrolidine)
`
`
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`Table 2.3 Nonclassical Bioisosteres”
`1.
`Carbonyl group
`
`OOP
`p<
`
`9i
`
`an
`
`n—CH—
`
`Q
`9
`Qo
`q
`n
`ni
`on SoeOH — POH — oe
`K
`nh
`OE:
`
`
`
`9
`il
`—— C—NH
`cn
`
`Hydroxy group
`0
`i
`“—-NHCR
`
`O.
`
`N
`
`‘OH
`
`OH
`
`fl
`
`o
`
`NON
`y
`OM,
`N
`
`H
`
`Q
`ul
` —CH,OH —NHCNH,
`
`-—NHSO,R
`
`2.
`
`3.
`
`4.
`
`Catechal
`
`HO
`
`5.
`
`Halogen
`
`H
`\
`N
`
`™O} OO OQ
`
`nO
`
`now no
`X=0,NR
`
`6,
`
`7.
`
`8.
`
`9.
`
`CF,
`
`CN
`
`NECN,
`
`CICN)y
`
`Thioether
`
`cN
`NC_CN
`Any A “Ny
`
`
`Thiourea
`i
`—xuSne
`Azomethine
`
`CN
`
`—NH*”
`
`“NH,
`
`—NH”
`
`|
`
`NO,
`
`“NH;
`
`¢N
`pe] -=
`Pyridine
`
`=
`
`CO
`
`N
`
`NO,
`
`a
`
`'@)
`
`ye
`R
`
`+
`NRy
`
`10.
`
`Me
`
`Spacer group
`Fem]
`Hydrogen
`
`-O-
`
`[FJ
`
`F
`
`—NHCN=—CHICN),
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`24
`il, Drug Development: Lead Modification
`bioisosteres do not have the same number of atoms and do notfit the steric
`and electronic rules of the classical isosteres, but they do produce a similarity
`in biological activity. Examples of these are shownin 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 interchange”6; some examples are shownin 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
`—CH,CH;— bioisosteres, then dibenzazepine antidepressant drugs (2.35)
`result.
`
`2.35
`
`It is, actually, quite surprising that bioisosterism should be such a success-
`ful approachto lead modification. Perusal ofTable 2.2, and especially of Table
`2.3, makesit clearthat in making a bioisosteric replacement, one or more of
`the following parameters will change: size, shape, electronic distribution,
`lipid solubility, water solubility, pK,, 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. If the 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, pK, 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 effective. 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 reducingits ability to
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`22
`
`2. Drug Discovery, Design, and Development
`
`Table 2.4 Examples of Bioisosteric Analogs*4?¢
`
`1.
`
`Neuroleptics
`
`(antipsycnotics)
`
`
`
`1
`X= ZN or CHCN
`
`N
`
`Y
`
`NH
`
`2.
`
`Anti-inflammatory agents
`
`x
`
`O
`\\—CH,
`N
`a»
`Oo
`
`OH
`
`Oo
`oo
`
`CHO.
`
`cl
`
`¥
`
`Z
`
`X = OH (indomethacin)
`
`= NHOH
`
`=
`
`N-N
`1 N
`H
`
`Y=CH,O z=
`
`Y=F
`
`Z = SCH, (sulindac)
`
`3.
`
`Antihistamines
`
`R—X— (CH), —Y
`
`X = NH,O,CH,
`
`Y=N(CH), (= 2)
`
`N
`
`—u\ (n= 1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`
`
`
`
`NNH N
`
`oy=
`
`f° = 1, 2)
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`Il, 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
`modifications 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 beganto 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.”
`
`E. Quantitative Structure-Activity Relationships
`
`1. Historical
`The concept of quantitative drug design is based on the fact that the biological
`properties of a compoundare a function ofits 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. Thefirst attempt to relate a physicochemical parame-
`ter to a pharmacological effect was reported in 1893 by Richet.*° He observed
`that the narcotic action of a group of organic compoundswasinversely related
`to their watersolubility (Richet’s rule). Overton?! and Meyer”related tadpole
`narcosis induced by a series of nonionized compoundsaddedto the waterin
`which the tadpoles were swimming to the ability of the compoundsto parti-
`tion between oil and water. These early observations regarding the depressant
`action of structurally nonspecific drugs were rationalized by Ferguson.*? 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-
`dynamicactivity 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 Hanschetal.*4 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 anat-
`
`
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`2. Drug Discovery, Design, and Development
`
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