Isosterism and Molecular Modification in Drug Design
`
`By C. W. Thornber
`IMPERIAL CHEMICAL INDUSTRIES LIMITED, PHARMACEUTICALS
`DIVISION, MERESIDE, ALDERLEY PARK, MACCLESFIELD,
`CHESHIRE, S K l O 4TG
`
`1 Introduction
`The idea of isosterism goes back to Langmuirf in 1919. At that time the word
`isosterism was used to describe the similarity of molecules or ions which have the
`same number of atoms and valence electrons e.g. 02-, F-, Ne. Clearly only
`those isosteres with the same nett charge show similar chemical and physical
`properties. Grimm2 enunciated his hydride displacement law to describe the
`similarity between groups which have the same number of valence electrons but
`different numbers of atoms. For example some similarities are present in the
`sequence: CH3, NH2, OH, Hal.
`Grimm’s hydride displacement law points out some similarities of size in
`groupings based on elements in the same row of the periodic table. Other similar-
`ities to be found in the periodic table are within the groups, where chemical
`reactivities are similar but with electronegativity decreasing as atomic weight
`increases and lipophilicity and polarizability increasing with the size of the
`atom. Other relationships exist in diagonal lines across the periodic table where
`atoms of similar electronegativity such as nitrogen and sulphur, oxygen and
`chlorine are found.
`In trying to relate biological properties to the physical and chemical properties
`of atoms, groups, or molecules, many physical and chemical parameters may be
`involved and the simple relationships mentioned above are clearly inadequate
`for this purpose. Friedman3 introduced the term ‘bioisosterism’ to describe the
`phenomenon in which compounds which are related in structure have similar or
`antagonistic properties. The use of the word isosterism has clearly outgrown its
`original meaning when used in medicinal chemistry and a loose flexible definition
`could be adopted such as: ‘Bioisosteres are groups or molecules which have
`chemical and physical similarities producing broadly similar biological pro-
`perties’.
`The term non-classical isosterism is also used interchangeably with bioisoster-
`ism, particularly in connection with isosteres which do not have the same number
`of atoms but do produce a similarity in some key parameter of importance in
`
`1 I. Langmuir, J. Amer. Chem. Soc,, 1919, 41, 868, 1543.
`8 H. G. Grimm, Z. Elektrochem., 1925,31,474; 1928, 34,430; 1934, 47, 53, 594.
`3 H. L. Friedman, ‘Influence of Isosteric Replacements upon Biological Activity’, National
`Academy of Sciences-Natianal Research Council Publication No. 206. Washington
`D.C., 1951, p. 295.
`
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`Isosterism and Molecular Modification in Drug Design
`that series. For example4 the two fg-adrenergic stimulants compounds (1) and
`(2) have similar activity.
`
`The concept of bioisosterism has been described in reviews by Burger,sa
`Schatz,5b Foye,6 Korolk~vas,~ Ariens,8 and H a n s ~ h . ~ This present review
`collates and extends the earlier observations with more recent reports from the
`literature and suggests new techniques for exploiting the concept.
`The ‘classical’ isosteres as defined by Burger5 and Korolkovas7 are given in
`Table 1.
`Table 1
`Univalent atoms and groups
`F
`
`Me
`
`C1
`
`OH
`SH
`I
`Br
`
`NH2
`PH2
`But
`Pri
`
`Bivalent atoms and groups
`
`S
`0
`COSR
`CO2R
`Tervalent atoms and groups
`-N,
`-p=
`Quadrivalen t a toms
`I
`-C- I
`
`CH2
`Se
`COCHzR CONHR
`
`H
`-N-
`
`-CH=
`-AS=
`I
`C i -
`
`S
`=N-
`
`e.g. benzene : thiophen
`e.g. benzene: pyridine
`
`Ring equivalents
`-CH=CH-
`=C-
`H
`-0-
`-NH-
`-CH?
`-S-
`4 A. A. Larson and P. M. Lish, Nature, 1964, 203, 1283.
`sa A. Burger in ‘Medicinal Chemistry’ 3rd Edn., ed. A. Burger, Wiley-Interscience, New York,
`1970.
`Sb V. B. Schatz in ‘Medicinal Chemistry’ 2nd Edn., ed. A. Burger, Wiley-Interscience, New
`York, 1960.
`6 W. 0. Foye, ‘Principles of Medicinal Chemistry’, Lea and Febiger, Philadelphia, 1970.
`A. Korolkovas, ‘Essentials of Molecular Pharmacology: Background for Drug Design’,
`Wiley, 1970.
`8 E. J. Ariens in ‘Drug Design’, ed. E. J. Ariens. Academic Press, New York, 1971, Vol. 1.
`C. Hansch, Intra-Science Chem. Rep., 1974, 8, 17.
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`C. W. Thornber
`
`2 Bioisosterism in Molecular Modification
`In the process of developing a lead compound, an antagonist to a known
`agonist, or an anti-metabolite from a known substrate, a large number of
`systematic molecular modifications will be made. The modern concept of
`bioisosterism can be an aid to the design of such modifications. In making a
`bioisosteric replacement the following parameters of the group being changed
`could be considered :
`(a) Size.
`(b) Shape (bond angles, hybridization).
`(c) Electronic distribution (polarizability, inductive effects, charge, dipoles).
`(d) Lipid solubility.
`(e) Water solubility.
`tfl PKa.
`(g) Chemical reactivity (including likelihood of metabolism).
`(h) Hydrogen bonding capacity.
`It is unlikely that any bioisosteric replacement will leave all these parameters
`undisturbed. The extent to which the replacement is useful will depend upon
`which of these parameters is important and which ones the bioisostere can best
`mimic.
`The element of a molecule being modified may have one or more of the follow-
`ing roles.
`(i) Structural. If the moiety has a structural role in holding other function-
`alities in a particular geometry, parameters such as size and bond angle will be
`important. The moiety may be buried deep in the molecule and have little
`contact with the external medium.
`(ii) Receptor interactions. If the moiety to be replaced is concerned with a
`specific interaction with a receptor or enzyme its size, shape, electronic
`properties, PKa, chemical reactivity, and hydrogen bonding will be the
`important parameters.
`(iii) Pharmacokinetics. The moiety to be replaced may be necessary for the
`absorption, transport, and excretion of the compound. In this case lipophili-
`city, hydrophilicity, hydrogen bonding, and PKa are likely to be important.
`(iv) Metabolism. The moiety may be involved in blocking or aiding meta-
`bolism. In this case chemical reactivity will be an important parameter. For
`example chloro and methyl substituents on a benzene ring may be inter-
`changeable for certain purposes but the toluene derivative can be metabolized
`to a benzoic acid and may therefore have a shorter half-life or unexpected
`side effects.
`Usually one will not know which role(s) the various parts of the molecule
`play(s) in its action and this determination will be part of the structure-activity
`study. However, from the simple considerations listed above it is clear that :-
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`lsosterism and Molecular Modification in Drug Design
`
`(A) A given molecular modification may allow some, but probably not all of
`the parameters (a)-(h) to be kept the same.
`(B) Whether the same or a different biological activity results from the replace-
`ment will be governed by the role(s) which that moiety fulfils in the molecule
`and whether parameters affecting that role have been disturbed.
`(C) From (A) and (B) it follows that what proves to be a good bioisosteric
`replacement in one series of compounds will not necessarily be useful in
`another.
`Completely identical properties are rarely sought and will in any case be
`difficult if not impossible to achieve. What we are more likely to be seeking is a
`subtle change in the molecule which will leave some properties the same and
`some different in order to improve potency, selectivity, absorption, duration, and
`toxicity. Bioisosteric replacements allow molecular modifications, in which the
`number of variables changed are limited. Arienss and Korolkovas7 have tried to
`introduce the idea of partial bioisosteric groups as those which turn an agonist
`into an antagonist. Although their lists of groups may be suggestive to the drug
`designer, the idea is probably incorrect because of the statement (C) above. An
`‘antagonist’ group in one molecule will only antagonize a similar ‘agonist’ group
`in another molecule if the agonist groups in both series are performing the same
`function. If an isosteric replacement results in a molecule which has some
`properties similar to the parent molecule but some important property has
`changed, it may be possible to compensate for this undesirable change by modifi-
`cations elsewhere in the molecule. For example a molecular modification may
`reduce the lipid solubility of the molecule thereby affecting its absorption,
`transport, and apparent potency. Optimum activity may be regained by inserting
`lipophilic groups into the molecule at some sterically undemanding site. Con-
`sequently the best compounds in this parallel series of isosteres, such as for
`example furans and thiophens, are likely to have different substituent patterns,
`
`3 The Mathematical Formulation
`The arguments used above can be expressed in the mathematical form used by
`HanschlO for the case where a simple substituent is being varied, for example on a
`benzene ring. If the potency of a drug is a function of several parameters of the
`substituent then:
`= 4 4 + H4 + C(Er5)
`where Hansch’s T value is used for the lipophilic character, Hammett’s (T value
`for the electronic property, Taft’s steric parameter to denote the size of the
`group and c is the concentration of drug required to achieve a given effect.
`If such a relationship were found for a drug series in which the constants B
`and C were zero then the potency would be a function of T only. In this context
`groups would be bioisosteric if they have similar T values independent of their
`10 C. Hansch, Accounts Chem. Res., 1969, 2, 232.
`
`1%:
`
`1
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`

`C. W. Thornber
`(3 and Es values. If however the three constants A, B, and C are all significant a
`much more limited range of equivalent groups will be available.
`If a series of compounds has more than one property, as is usual, then more
`than one equation will be needed to describe the effects of changing the sub-
`stituent :
`
`Clearly if A = D, B = E, and C = F, etc., no selectivity can be found within
`this limited series. If however C< F then for the desired activity Es is not import-
`ant and 7r and 0 may be optimized while reducing the value of Es, thereby
`reducing the side effects. This phenomenon of increasing selectivity by bio-
`isosteric replacement relies upon the fact that some desirable properties in the
`molecule can be retained when unimportant parameters can be varied. An un-
`important parameter for the biological activity desired may be a key parameter in
`the side effect.
`Thus bioisosteric replacements are useful in searching for potency, selectivity,
`absorption, and duration. Following the Hansch treatment one could produce a
`modern definition of bioisosterism based upon measurable parameters such as
`T , 0, Es, hydrogen bonding properties, pKa, etc., and Hanschg has used the term
`‘isolipophilic’ for groups with the same 7r value.
`Table 2 shows some functional groups with similar electron-withdrawing
`properties. If electronic effects alone influence the biological activity in a series of
`drugs then these groups would be equivalent. If, however, the lipophilicity and
`steric factors are important then absolute identity cannot be achieved.
`
`Table 2
`
`Functional Group
`F
`CI
`Br
`I
`CF3
`SCFa
`COMe
`CHO
`CO2Me
`CHSH-NO2
`
`ES
`0.78
`9.27
`0.08
`-0.16
`-1.16
`
`Om
`0.34
`0.37
`0.39
`0.35
`0.43
`0.40
`0.31
`0.36
`0.32
`0.32
`
`7r
`0.14
`0.71
`0.86
`1.12
`0.88
`1.44
`-0.55
`-0.65
`-0.01
`0.11
`
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`Isosterism and Molecular Modification in Drug Design
`
`Extensive tables of uy T , and Es values are now available.11 These can be used
`to gain a more quantitative idea of some aspects of isosterism using the better
`known functional groups.
`
`4 Chemical Reactivity
`Biological effects are generally produced by ‘weak’ interactions between the drug
`and the receptor but covalent bonding does occasionally play a part. A series of
`aspirin isosteres (3) was reported in 1975.12 The nitrogen, sulphur, and carbon
`
`MeCOX
`
`(3) X = 0, NH,
`S, or CH,
`
`isosteres were all totally inactive despite the classical purity of the replacements
`tried. Now that it is known that aspirin is an acetylating agent for prostaglandin
`synthetase this result is more readily understood.13 The agents are widely differ-
`ent in their ability to act as acylating agents unless other substantial modifica-
`tions are made in the molecules.
`
`5 Non-classical Isosteres : Some Further Points
`In considering bioisosterism in its widest sense it should be noted that similar
`effects in two functional groups need not imply atom upon atom overlap.
`Edwards14 has pointed out that a common enzyme or receptor interaction in-
`volves hydrogen bonding to a carbonyl group. Strong hydrogen bonds may be
`formed to the carbonyl oxygen by hydrogen atoms within a cone having an angle
`of about 60” at its apex. Two molecules RXH and RAXH, where A is an addi-
`tional atom, may be able to bind to the active site without identical positioning
`of the X or H. In addition the conformational mobility in both the drug and the
`receptor molecule will allow essentially similar binding of two drugs without the
`need to consider that the binding groups on the drugs are positioned in space
`in an identical manner.
`
`list shown in Table 3 is drawn from
`Examples of Non-classical 1sosteres.-The
`earlier reviews5-9 and from the examples given in Table 4 at the end of this
`
`l1 Tables of substituent constants can be found in the following papers. C Hansch, S. D.
`Rockwell, P Y. C. Jow, A. Leo, and E. E. Steller, J. Med. Chem., 1977, 20, 304; J. G.
`Topliss, J. Med. Chem., 1972,15, 1006, and 1977,20,463; C. Hansch, A. Leo, S. H. Unger,
`Ki Hwan Kim, D. Nikaitoni, and E. J. Lien, J Med. Chem., 1973,16, 1207.
`l 2 L. Thompkins and K. H. Lee, J. Pharm. Sci., 1975. 64, 760.
`l a G. J. Roth, N. Stanford, and P. W. Majerus, Proc. Nat. Acad. Sci, U.S.A., 1975,72, 3073.
`l4 P. N. Edwards, I.C.I. Pharmaceuticals Division, personal communication.
`
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`
`review. In addition a few p r o p o ~ a l s l ~ - ~ ~ which have not yet been realized in
`medicinal chemical work are included.
`
`C. W. Thornber
`
`Table 3
`
`Carbotryl group
`
`‘c=c
`0
`
`ref. 15
`
`Carboxylic acid group
`
`ICN
`‘SO
`
`‘CN ’
`
`\
`,SO,
`
`R
`I
`-SO,N-
`
`0
`II
`-CN-
`I
`
`CN
`I
`-CH-
`
`CO,H
`
`S0,NHR
`
`SO,H
`
`PO(OH)NH,
`
`PO(0 H)OE t
`
`G O H klol?J
`
`CONHCN
`
`ref, 16
`
`Hydroxy-group
`
`OH
`
`NHCOR
`
`NHS0,R
`
`CH,OH
`
`NHCONH,,
`
`NHCN
`
`ref. I6
`
`CH( C N )
`
`ref. 16
`
`Catechol
`
`Halogen
`
`x=o
`X=NR
`
`Halogen
`
`CF,
`
`CN
`
`N(CN),
`
`C(CN),
`
`ref. 16, 17
`
`K. Wallenfels, K. Friedrich, J. Rieser, W. Ertel, and H. K. Thieme, Angew. Chem. Internat.
`Edn., 1976, 15, 261.
`1 6 H. von Kohler, B. Eichler, and R. Salewski, 2. anorg. Chem., 1970, 379, 183, also includes
`other possibilities in the sulphur and phosphorus and nitro acid series.
`l7 K. von Wallenfels, Chimiu, 1966, 20, 303.
`
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`Isosterism and Molecular Modification in Drug Design
`
`Table 3 continued
`Thioether
`CN
`
`Thiourea
`
`NCN
`II
`NH-C-NH,
`
`NH -C-NH,
`
`Azomethine
`
`-N=
`
`Pyridine
`
`CN \c2N
`/ \
`
`ref. 16
`
`CHNO,
`II
`NH -C-NH2
`
`ref. 17
`
`I
`CN
`-c=
`
`Q
`NO, Q
`
`R
`
`7 NR,
`
`Spacer groups
`
`In addition ring-opened forms of molecules may be considered to be isosteric
`with the corresponding ring-closed forms although the conformation of the
`seco form will be unlike the parent molecule. However, if in ring opening an
`atom is removed a conformation similar to the parent molecule may be possible.
`
`6 Substructure Searching and Bioisosterism
`Although the classical Hansch approach is used largely for optimization within
`a series, molecular modifications based on bioisosterism principles can generate
`new series or even develop new leads if an agonist is used as the starting point for
`the design of an antagonist. One aid to this process is the use of a compound
`collection and computer techniques for doing substructure searches, e.g. the
`
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`C. W. Thrnber
`
`Crossbow suite of programmes.18 For example suppose that random screening
`has turned up the lead (4). One may consider bioisosteric replacements for
`the ring, the oxygen, the polymethylene chain, or the amidic moiety, and design
`a substructure search for compounds of type (5). A vast number of permutations
`are possible and from these compounds may be available for tests which result
`in new leads which have properties worth exploiting, such as perhaps (6).
`
`.*"O/NHCONHM~
`
`Y - (CH R)nN H -Z
`
`(5) X = CH=CH, CH-N,
`S, 0, or NR
`Y = 0, S, SO, SO,, Se, NCN, or NCOR
`n = 2, 3, or 4
`R = H or alky1,including forming a ring
`Z= COR, C02R, SOR, SO,R, or CONHR
`A=B= defined substituents
`
`Me
`
`N
`
`(6)
`literature of medicinal chemistry is rich in examples of the use
`Examples.-The
`of the concept of bioisosterism and the reader is referred to the reviews men-
`tioned5-8 and the references quoted therein for examples reported before 1970.
`There follows a brief discussion of bioisosteres of some indole-amines which has
`some useful lessons, and Table 4 lists examples culled from the literature since
`1970. Only the structures are given in this Table as an illustration of the kinds
`of change which have been useful. The reader is referred to the original papers
`for the full details of biological activity and selectivity. The list is not compre-
`hensive but represents some uses of more novel non-classical types. Rudinger19
`has reviewed isosteric replacements in the field of peptide chemistry up to 1971
`and some further discussions20 have been published recently.
`
`Indole-amines.-Campaigne21 has studied and reviewed the work on bioisosteres
`of 5-hydroxytryptamine (7) and one or two details of the work are instructive.
`Whereas (8) was inactive as an agonist or antagonist on the rat uterus preparation,
`the corresponding tryptophan analogue (9) had weak activity as an enzyme
`inhibitor for 5-hydroxytryptamine decarboxylase.22 This type of bioisostere
`E. E. Townsley and W. A. Warr, 'Chemical and Biological Data; An Integrated On-Line
`Approach' in 'Retrieval of Medicinal Chemical Information', ed. Howe, Milne, and Pennell
`(A. C. S. Symposium Series No. 84), American Chemical Society, Washington D.C.
`l 8 J. Rudinger, in ref. 8, Vol. 11, Chapter 9.
`* O Further discussion of peptide backbone replacement is found in ref. 19 and W. Soudyn and
`I. van Wijngaarden, in 'Biological Activity and Chemical Structure', ed. J. A. Keverling
`Buisman, Elsevier, Holland, 1977; a peptide link isostere -CH2-S-
`has been reported
`by J. A. Yankeelov, Kam-Fook Fok, and D. J. Carothers, J. Org. Chem., 1978,43, 1623.
`* l E. Campaigne, R. P. Maichel, and T. R. Bosin, Medicinal Chemistry, Specialist Con-
`tributions, 3rd International Symposium, 1972, Butterworths, 1973, p. 65.
`z 8 M. Pigini, M. Gianella, F. Gualtieri, C. Melchiorne, P. Bolle, and L. Angelucci, European
`J. Med. Chem., 1975, 10, 29, 33.
`
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`Isosterisni and Molecular Modification in Drug Design
`
`(7) R = M (5-hydroxytryptamine)
`(10) R = CO,H (5-hydroxytryptnphan)
`
`(8) R = H
`(9) R = CO,H
`
`loses all affinity for the 5-hydroxytryptamine (5-HT) receptor but retains it in
`part for an enzyme system. Similarly, in the series of compounds 5-HT, (1 l), (12),
`and (13) activity has been measured against the rat fundic strip preparation and
`on the enzyme caerulopla~min.~~ Whereas 5-HT is a substrate for the enzyme,
`compound (1 1) inhibited caeruloplasmin’s oxidation of 5-HT and noradrenaline.
`
`NH,
`
`Rat Fundic Strip
`X Intrinsic
`activity
`1
`5-HT NH
`CH2 0.96
`(11)
`(12)
`0
`0.84
`(13)
`1.08
`S
`
`PDa
`
`7.6
`5.6
`4.6
`6.1
`
`Compound (1 2) inhibits only 5-HT oxidation and compound (1 3) was inactive as
`a substrate or an antagonist. This would appear to demonstrate that for the
`enzyme system the imino grouping at the l-position of the ring is essential.
`On the rat fundic strip, however, all the analogues have full agonist activity
`though with reduced potency, demonstrating that the 5-HT receptor has a
`greater tolerance for loss of the imino nitrogen. These simple experiments demon-
`strate the role of bioisosteric replacements in exploring selectivity between
`different receptors and enzymes.
`
`a3 B. C. Barrass, D. B. Goult, R. M. Pinder, and M. Sheels, Biuchem. Pharmacol., 1973, 22,
`2891.
`
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`Table 4 Some recent examples oj'bioisosterism
`
`Dih ydroxyplmy la Janine analogues
`
`C. W. Thornber
`
`Dopa
`
`Mimosine ref. 24
`
`oFco2H
`
`HO
`
`\ NH NH.2
`
`ref. 25
`
`ref. 26
`
`ref. 27
`
`Histamine H-2 antagonists
`
`Me,
`
`-
`
`,"H
`
`H N v / N
`
`H
`I
`,SCH ,CH ,N
`
`I IfNHMe
`
`X
`
`X = S or NCN ref. 2s
`
`X
`X = NCN or CHNO, ref. 29
`
`H. Haguchi, Mol. Pharmacol., 1977, 13, 362.
`A natural product from Streptomyces species, S . Inoue, T. Shamura, T. Tsurvoka, Y.
`Ogawa, H. Watanabe, J. Yoshidea, and T. Nuda, Chem. and Pharm. Bull. (Japan), 1975,
`23, 2669.
`Synthesized as a mimosine analogue, R. N. L. Harris and R. Teitei, Austral. J. Chem.,
`1977, 30, 649.
`s 7 S. J. Norton and E. Sanders, J. Med. Chem., 1967,10, 961.
`R. W. BrimbIecombe, W. A. M. Duncan, C. 3. Durant, J. C. Emmett, C. R. Ganneiin, and
`M. E. Parsons, J. Znt. Med. Res. 1975, 3, 86. See also Sulphur-methylene isosterism in the
`development of metiamide, J. W. Black, G. J. Durant, J. C. Emmett, and C. R. Gannelin,
`Nature, 1974,248, 65, and C. R. Gannellin, J. Appl. Chem. Biotechnol., 1978,28, 183.
`Alien and Hanbury, U.S.P. 4 128 658.
`
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`Isosterism and Molecular Modification in Drug Design
`
`Table 4 continued
`
`Neuroleptics
`
`0
`11
`X =
`NC\
`
`or CH-CN
`
`ref. 30
`
`Anthelmintics
`
`ref. 31
`
`@-A drenergic blockers
`
`X = S or Se ref. 32
`
`OH
`
`NHPr'
`
`e
`
`R
`
`NHPr'
`
`
`R
`
`-
`
`E
`
`
`
`ref. 33
`
`9 o Boehringer, Sohn C. H., U.S.P. 4 085 216.
`.3L H. Fisher and M. Lusi, J. Med. Chem., 1972,15,982; R. J. Bochis, R A. Dybas, P. Eskola,
`P. Kulsa, B. 0. Linn, A. Lusi, E. Mutzner, J. Milkowski, H. Mrozik, L. E. Olen, L. H.
`Peterson, R L. Tolman, A. F. Wagner, F. S. Waksmunski, J. R. Egerton, and D. A.
`Osteind, J. Med. Chem., 1978, 21, 235.
`R. N. Hanson, R. N. Giese, M. A. Davis, and S. M. Costello, J . Med. Chem, 1978, 21,
`496.
`3 3 T. Jen, J. S. Frazee, M. S. Schwartz, K. F. Erhard, C. Kaiser, D. F. Colella, and J. R.
`Wardell, J. Med. Chem., 1977, 20, 1263.
`
`574
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`
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`SAWAI EX. 1017
`Page 12 of 18
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`

`

`p- A drenergic s rimulan ts
`
`C. W. Thornber
`
`R = Me, X = OH Adrenaline
`R = But, X = CH,OH
`Salbutamol ref. 34
`R = But, X = NHCONH,
`Carbuterol ref. 35
`R = Pr', X = NHS0,Me
`Soterenol ref. 36
`
`OH
`
`N HPri
`
`H
`
`ref. 38
`
`NHPr'
`
`Clenbuterol
`
`ref. 37
`
`NHPri
`
`ref. 39 FNHR
`
`ref. 39
`
`HN 0
`
`ref. 40
`
`3 4 D. Hartley, D. Jack, L. H. Lunts, and A. C. Ritchie, Nature, 1968, 219, 861 ; D. T. Collin,
`D. Hartley, D. Jack, L. H. C. Lunts, J. C. Press, A. C. Ritchie, and P. Toon, J. Med. Chem.,
`1970, 13, 674.
`3 b C. Kaiser, J. Med. Chem., 1974, 17, 49.
`asA. A. Larsen, W. A. Gould, H. R. Roth, W. T. Comer, R. H. Uloth, K. W. Dungan, and
`P. M. Lish, J. Med. Chem., 1967,10,462.
`3 7 J. Keck, G. Kruger, K. Noll, and H. Machleidt, Arzneimittelforsch., 1972, 22, 861.
`C. D. Arnett, J. Wright, and N. Zenker, J. Med. Chem., 1978, 21, 72.
`%* H. W. R. Williams, Canad. J. Chem., 1976, 54, 3377.
`4 0 S. Yoshizaki, K. Tarimura, S. Tamada, Y. Yabuuchi, and K. Nakagawa, J. Med. Chem.,
`1976,19, 1138.
`
`575
`
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`
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`SAWAI EX. 1017
`Page 13 of 18
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`

`

`Isosterism and Molecular Modification in Drug Design
`
`Table 4 continued
`
`Vusoilila tors
`
`X = 0 or S, Y = SO2 ref. 41
`x = 0 ,
`Y = CO ref. 42
`x = s,
`Y = CO
`ref. 43
`
`X = C0,Me
`X = S0,Me
`
`ref. 44
`ref. 45
`
`OAc
`
`rl, rl,
`
`
`X = S or NCN X = S or NCN
`
`
`
`ref. 46 ref. 46
`
`41 SmithKline Corp., U.S.P. 4 117 128.
`4 a E. M. Vaughan Williams and P. Polster, European J. Pharmacol., 1974, 25, 241 ; Unlisted
`Drugs., 1971, 23, (81, 110.
`4 3 N . Claeys, C. Goldenberg, R. Wandestrick, E. Devay, M. Descamps, G. Delaunois, J.
`Bauthier, and R. Charlier, Chim. Ther., 1972, 7, 377.
`4 4 F. Bossert, and W. Vater, Naturwiss., 1971, 58, 578; Drugs of Today, 1975, 11, 154.
`4 5 Ciba-Geigy B.P. 1 464 324.
`4 6 W.-H Chiu, T. H. Klein, and M. E. Wolff, J. Med. Chem., 1979. 22, 119.
`
`576
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`

`

`C. W. Thornber
`
`R
`
`< ,". ref. 49
`
`N-N
`
`N
`H
`
`Anti-injkmmatory
`
`CH,-X
`
`Me
`
`H
`X = CO,H
`
`ref. 48
`
`Ornithine decarboxylase inhibitor
`
`x = CO,H or
`
`ref. SO
`
`0
`
`Gabergic agents
`
`NO& W N H ,
`
`
`
`HO,S-NH,
`
`ref. 53
`
`ref. 51
`
`ref. 52
`
`47 P. F. Juby and T. W. Hudyma, J. Med. Chem., 1969, 12, 396.
`4 8 T. Y. Shen, R. L. Ellis, T. B. Windholz, A. R. Matzuk, A. Rosegay, S. Lucas, B. E. Witzel,
`C. H. Stammer, A. N. Wilson, F. W. Holly, J. D. Willet, L. H. Sarett, W. J. Holtz, E. A.
`Risley, G. W. NUSS, and C. A, Winter, J. Amer. Chem. Soc., 1963, 85, 488.
`4 9 D. J. Drain, B. Davy, M. Horlington, J. G. B. Howes, J. M. Scruton, and R. A. Selway, J.
`Pharm. Pharmacol., 1971, 23, 857.
`6 o P. Bey, C. Danzin, V. van Dorsselaer, P. Mamont, M. Jung, and C. Tardiff, J. Med. Chern.,
`1978, 21, 50.
`61 J. G. Atkinson, Y. Giraud, J. Rokach, C. S. Rooney, C. S. McFarlane, A. Rackham, and
`N. N. Share, J. Med. Chem., 1979, 22, 99.
`a x D. R. Curtis, A. W. Duggan, D. Felix, and G. A. R. Johnston, Brain Res., 1971, 32, 69.
`63 D. R. Curtis and J. C. Watkins, Nature, 1961,191, 1010.
`
`577
`
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`SAWAI EX. 1017
`Page 15 of 18
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`

`

`Isosterism and Molecular Modification in Drug Design
`
`Table 4 continued
`
`Prostaglandin ring system
`
`L_,
`ref. 54
`
`0
`ref. 56
`
`Me
`
`.o
`
`I .."Y
`
`8,-
`H2N
`I
`
`ref. 55
`
`ref. 55
`
`ref. 54
`
`0%
`
`M+NO I
`
`ref. 58
`
`."c
`ref. 57 LN/
`I
`Me'sx
`
`'0 0
`\ /
`
`ref. 60
`
`ref. 60
`
`ref. 61
`
`8 4 P. A. Zoretic, P. Soja, and T . Shiah, Prostaglandins, 1978, 16, 555.
`6 5 P. A. Zoretic, P. Soja, and T. Shiah, J. Med. Chem., 1978, 21, 1330.
`56 C. J. Harris, N. Whittaker, G. A. Higgs, J. M. Armstrong, and P. M. Reed, Prostaglandins,
`1978, 16, 773.
`6 7 J. H. Jones, W. J. Holtz, J. B. Bicking, E. J. Cragoe, R. Mandel, and F. A. Kuehl, J. Med.
`Chem., 1977,20, 1299.
`8 8 J. B. Bicking, C. M. Robb, R. L. Smith, E. J. Cragoe, F. A. Kuehl, and L. R. Mandel,
`J. Med. Chem., 1977, 20, 35.
`6 D J. H. Jones, W. J. Holtz, J. B. Bicking, E. J. Cragoe, L. R. Mandel, and F. A. Kuehl,
`J . Med. Chem., 1977, 20, 44.
`6 o R. L. Smith, J. B. Bicking, N. P. Gould, T.-J. Lee, C. M. Robb, F. A. Kuehl, L. R. Mandel,
`and E. J. Cragoe, J. Med. Chem., 1977,20, 540.
`81 T. A. Eggelte, H. de Koning, and H. 0. Huisman, Rec. Trav. chim., 1977, 96,271.
`
`578
`
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`Page 16 of 18
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`

`

`C. W. Thornber
`
`ref. 62
`
`ref. 63
`
`ref. 53
`
`0
`
`ref. 63
`
`ref. 64
`
`ref. 65
`
`0
`
`ref. 66
`
`ref. 67
`
`HO ("y Hoa
`
`ref. 68
`
`0
`
`ref. 69
`
`ref. 70
`
`ref. 71
`
`ref. 72
`
`@ a P. A. Zoretic, B. Branchard, and N. D. Sirka, J. Urg. Chem., 1977, 42, 3201; J. Bruin,
`H. de Koning, and H. 0. Huisman, Tetrahedron Letters, 1975, 4599; G. Bollinger and
`I. M. Muchowski, Tetrahedron Letters, 1975, 2931.
`63 R. L. Smith, T.-J. Lee, N. P. Gould, E. J. Cragoe, H. G. Oien, and F. A. Kuehl, J. Med.
`Chem., 1977, 20, 1292.
`8 4 Merck, U.S.P., 4 087 435.
`6 K Beechams, Belgian P., 861 956.
`66 Beechams, Belgian P., 861 957.
`Miles, U.S.P., 4 2 7 612.
`6 8 Pfizer, U.S.P., 4 132 847.
`eu J. Vlattas and L. Dellavecchia, Tetrahedron Letters, 1974, 4459.
`'O J. Vlattas and L. Dellavecchia, Tetrahedron Letters, 1974, 4455.
`5 1 Tanabe Seijaku, G.P., 2 229 225; F. M. Hauser and R. C. Huffman, Tetrahedron Letters.
`1974, 905.
`5 * J. T. Harrison, R. J. K. Taylor, and J. H. Fried, Tetrahedron Letters, 1975, 1165.
`
`579
`
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`SAWAI EX. 1017
`Page 17 of 18
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`

`

`sosterism and Molecular ModificL7tion in Drug Design
`
`Table 4 continued
`
`Prostaglandin ring system (continued)
`
`ref. 73
`
`ref. 74
`
`ref. 75
`
`ref. 76
`
`7 3 J. T. Harrison, V. R. Fletcher, and J. H. Fried, Tetrahedron Letters, 1974, 2733.
`7 4 E. 1. du Pont de Nemours, B.P., 1 428 431.
`7 5 J. T. Harrison and V. R. Fletcher, Tetrahedron Letters., 1974, 2729.
`7 a A . P. Bender, J. Med. Chem., 1975, 18, 1094.
`
`580
`
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`SAWAI EX. 1017
`Page 18 of 18
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`