BIOMEDICAL LIBRARY
`
`_idIIIM
`
`80
`
`LO
`
`Breckenridge Exhibit 1025
`Breckenridge v. Research Corporation Technologies, Inc.
`
`

`
`____
`
`Chemical Society Reviews
`
`Vol
`
`No
`
`1979
`
`TILDEN LECTURE
`
`Concerning Stereochemjcal Choice in Enzymic Reactions
`By
`Overton
`
`The Acidity of Solid Surfaces and its Determination
`by Amine Titration and Adsorption of Coloured
`Indicators
`
`By
`
`Atkinson and
`
`Curthoys
`
`Non-isoprenoid Long Chain Phenols
`By
`
`Tyman
`
`Some New N.M.R Methods for Tracing the Fate of
`Hydrogen in Biosynthesis
`
`By
`
`Garson and
`
`Staunton
`
`Isosterism and Molecular Modification in Drug Design
`By
`Thornber
`
`1979 Indexes
`
`Page
`
`447
`
`475
`
`499
`
`539
`
`563
`
`581
`
`The Chemical Society London
`
`

`
`Chemical Society Reviews
`
`Chemical Society Reviews appears quarterly and comprises approximately 25
`articles ca 500 pp per annum It
`is intended that each review article shall be of
`interest to chemists in general and not merely to those with
`specialist interest
`in the subject under review The articles range over the whole of chemistry and
`its interfaces with other disciplines
`Although the majority of articles are intended to be specially commissioned
`the Society is always prepared to consider offers of articles for publication In
`such cases
`short synopsis rather than the completed article should be sub
`mitted to The Managing Editor Books and Reviews Section The Chemical
`Society Burlington House Piccadilly London W1V OBN
`Members of the Chemical Society may subscribe to Chemical Society Reviews
`at 6.00 per annum beginning 1980 7.50 per annum they should place their
`orders on their Annual Subscription renewal forms in the usual way
`Non-members may order Chemical Society Reviews for 16.00 $33 be
`ginning 1980 22.00 $50 per annum remittance with order from
`The Publications Sales Officer The Chemical Society Blackhorse Road
`Letchworth Herts SG6 1HN England
`
`Note to subscribers We regret
`the delays in publication of the 1979 issues
`CS Reviews
`The main causes were the long-term effects of shortages in sub
`mitted articles and production difficulties during earlier years Steps have been
`taken to rectify this distressing situation and the intention is to revert
`to the
`usual quarterly publication dates by the end of 1980 or the beginning of 1981
`
`Copyright reserved by The Chemical Society
`
`1980
`
`ISSN
`
`03060012
`
`Published by The Chemical Society Burlington House London WIV OBN
`Printed in England by Eyre
`Spottiswoode Ltd Thanet Press Margate
`
`

`
`Isosterism and Molecular Modffication in Drug Design
`
`By
`Thornber
`IMPERIAL CHEMICAL INDUSTRIES
`LIMITED PHARMACEUTICALS
`DIVISION MERESIDE ALDERLEY PARK MACCLESFIELD
`CHESHIRE SK1O 4TG
`
`Introduction
`The idea of isosterism goes back to Langmuir1 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
`Ne Cleariy only
`those isosteres with the same nett charge show similar chemical and physical
`properties Grimm2 enunciated
`law to describe the
`his hydride displacement
`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
`Grimms 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
`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
`similarity in some key parameter of importance in
`
`Amer Chem Soc 1919 41 868 1543
`Langmuir
`Grimm Elektrochem 1925 31 474 1928 34 430 1934 47 53 594
`Friedman Influence of Isosteric Replacements upon Biological Activity National
`Research Council Publication No 206 Washington
`Academy of SciencesNational
`D.C 1951
`295
`
`563
`
`

`
`isosterism and Molecular Modfication in Drug Design
`
`that series For example4 the two /3-adrenergic
`have similar activity
`
`stimulants compounds
`
`and
`
`CHOHCH2NHMe
`
`Cl-IOHCH2NHMe
`
`HO3
`
`MeSO2N
`
`pKa 9.6
`
`pKa 9.1
`
`The concept of bioisosterism has been described
`in reviews by Burgersa
`Schatz5b Foye6 Korolkovas7 Ariens8 and Hansch.9 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
`
`Table
`Univalent atoms and groups
`
`Bivalent atoms and groups
`
`Me
`
`Cl
`
`OH
`SH
`
`Br
`
`NH2
`PH2
`But
`
`Pr1
`
`CH2
`Se
`COSR COCH2R CONHR
`Tervalent atoms and groups
`
`CO2R
`
`CHAs
`
`Quadrivalent atoms
`
`C-
`
`Ring equivalentsCHCH
`
`-Si
`
`N.-
`S---- CH2 NH
`
`e.g benzene thiophen
`e.g benzene pyridine
`
`Larson and
`Lish Nature 1964 203 1283
`Burger in Medicinal Chemistry 3rd Edn ed
`Burger Wiley-Interscience New York
`1970
`
`Schatz in Medicinal Chemistry 2nd Edn ed
`5b
`York 1960
`Foye Principles of Medicinal Chemistry Lea and Febiger Philadelphia 1970
`Korolkovas Essentials of Molecular Pharmacology Background
`for Drug Design
`Wiley 1970
`Ariens in Drug Design ed
`Ariens Academic Press New York 1971 Vol
`Hanscb Jntra-Sclcnce Chem Rep 1974
`17
`
`Burger Wiley-Interscience New
`
`564
`
`

`
`Thornber
`
`Bioisosterism in Molecular Modification
`In the process of developing
`known
`lead compound an antagonist
`to
`agonist or an anti-metabolite from known substrate
`large number of
`be made The modern concept of
`systematic molecular modifications will
`bioisosterism can be an aid to the design of such modifications In making
`the following parameters of the group being changed
`bioisosteric replacement
`could be considered
`
`Size
`
`Shape bond angles hybridization
`
`Electronic distribution polarizability inductive effects charge dipoles
`
`Lipid solubility
`
`Water solubility
`
`pKa
`
`Chemical reactivity including likeithood of metabolism
`
`Hydrogen bonding capacity
`
`It
`
`is unlikely that any bioisosteric replacement will
`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 molecule being modffied may have one or more of the follow
`ing roles
`
`leave all
`
`interactions If
`
`the moiety to be replaced is concerned with
`receptor or enzyme its size shape electronic
`and hydrogen bonding will
`be the
`reactivity
`
`If the moiety has
`structural role in holding other function
`Structural
`alities in 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
`interaction with
`specific
`properties pICa chemical
`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
`benzene ring may be inter
`changeable for certain purposes but the toluene derivative can be metabolized
`benzoic acid and may therefore have
`to
`shorter half-life or unexpected
`side effects
`
`Usually one will not know which roles the various parts of the molecule
`plays in its action and this determination will be part of the structureactivity
`from the simple considerations listed above it
`is clear that
`study However
`
`565
`
`

`
`Isosterism and Molecular Modification in Drug Design
`
`the parameters ah to be kept
`
`given molecular modification may allow some but probably not all of
`the same
`
`Whether the same or
`different biological activity results from the replace
`ment will be governed by the roles which that moiety fulfils
`in the molecule
`and whether parameters affecting that role have been disturbed
`From
`replacement
`
`follows that what proves to be
`and
`good bioisosteric
`in one series of compounds will not necessarily be useful
`in
`
`it
`
`another
`
`Completely identical properties are rarely sought and will
`in any case be
`if not impossible to achieve What we are more likely to be seeking is
`difficult
`leave some properties the same and
`subtle change in the molecule which will
`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 Ariens8 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
`above An
`designer
`the idea is probably incorrect because of the statement
`antagonist group in one molecule will only antagonize
`similar agonist group
`the agonist groups in both series are performing the same
`in another molecule if
`function If an isosteric replacement
`molecule which has some
`results in
`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 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
`
`The Mathematical Formulation
`The arguments used above can be expressed in the mathematical
`form used by
`Hansch for the case where simple substituent
`is being varied for example on
`benzene ring If
`the potency of
`function of several parameters of the
`drug is
`substituent then
`
`log A7r
`
`Bor
`
`CE8
`
`where Hanschs ir value is used for the lipophilic character Hammetts
`value
`for the electronic property Tafts steric parameter
`to denote the size of the
`group and
`is the concentration of drug required to achieve
`given effect
`If such
`relationship were found for
`drug series in which the constants
`and
`were zero then the potency would be
`function of IT only In this context
`groups would be bioisosteric if
`they have similar IT values independent of their
`
`10
`
`Hansch Accounts Chem Res 1969
`
`232
`
`566
`
`

`
`and
`values If however the three constants
`and
`are all significant
`much more limited range of equivalent groups will be available
`series of compounds has more than one property as is usual
`If
`then more
`than one equation will be needed to describe the effects of changing the sub
`stituent
`
`Thornber
`
`log
`
`Air
`
`Bar
`
`CE8
`
`Desired activity
`
`log Dir Ea FE
`
`Side effects
`
`and
`
`etc no selectivity can be found within
`Clearly if
`this limited series If however
`then for the desired activity E8 is not import
`ant and ir and
`may be optimized while reducing the value of
`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
`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
`modem definition of bioisosterism based upon measurable parameters such as
`E8 hydrogen bonding properties pK etc and Hansch9 has used the term
`ir
`isolipophilic for groups with the same
`value
`shows some functional groups with similar electron-withdrawing
`Table
`properties If electronic effects alone influence the biological activity in 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
`
`Functional Group
`
`Cl
`Br
`
`CF3
`SCF
`COMe
`CHO
`CO2Me
`CHCHN02
`
`Es
`
`0.78
`
`9.27
`
`0.08
`0.16
`1.16
`
`IT
`
`0.14
`
`0.71
`
`0.86
`
`1.12
`
`0.88
`
`1.44
`0.55
`0.65
`0.01
`0.11
`
`0.34
`
`0.37
`
`0.39
`
`0.35
`
`0.43
`
`0.40
`
`0.31
`
`0.36
`
`0.32
`
`0.32
`
`567
`
`

`
`Isosterism and Molecular Modification in Drug Design
`
`Extensive tables of
`IT and E5 values are now available These can be used
`to gain more quantitative idea of some aspects of isosterism using the better
`known functional groups
`
`Chemical Reactivity
`Biological effects are generally produced by weak interactions between the drug
`and the receptor but covalent bonding does occasionally play
`series of
`part
`was reported in 1975.12 The nitrogen sulphur and carbon
`aspirin isosteres
`
`MeCOX
`
`3x
`
`NH
`or Cl-i2
`
`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.3 The agents are widely differ
`ent
`in their ability to act as acylating agents unless other substantial modifica
`tions are made in the molecules
`
`Non-classical Isosteres Some Further Points
`In considering bioisosterism in its widest sense it should be noted that similar
`effects in two functional
`imply atom upon atom overlap
`groups need not
`Edwards4 has pointed out
`common enzyme or receptor
`that
`interaction in
`volves hydrogen bonding to
`carbonyl group Strong hydrogen bonds may be
`formed to the carbonyl oxygen by hydrogen atoms within cone having an angle
`of about 60 at its apex Two molecules RXH and RAXH where
`is an addi
`tional atom may be able to bind to the active site without
`identical positioning
`In addition the conformational mobility in both the drug and the
`of the
`or
`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
`
`Examples of Non-classical Isosteres.The list shown in Table
`earlier reviews59 and from the examples given in Table
`at
`
`is drawn from
`the end of this
`
`1Tables of substituent constants can be found in the following papers
`Hansch
`Med Chem 1977 20 304
`Jow
`Rockwell
`Leo and
`Topliss Med Chem 1972 15 1006 and 1977 20463
`Leo
`Hansch
`Unger
`Ki Hwan Kim Nikaitoni and
`Med Chem 1973 16 1207
`Lien
`Pharm Sd 1975 64 760
`Thompkins and
`Lee
`Majerus Proc Nat Acad Sd U.S.A 1975 72 3073
`Roth
`Stanford and
`Edwards IC. Pharmaceuticals Division personal communication
`
`Steller
`
`12
`
`568
`
`

`
`few proposals5-7 which have not yet been realized in
`review In addition
`medicinal chemical work are included
`
`Thornber
`
`Table
`
`arbonyl group
`
`ref
`
`15
`
`Carboxylie acid group
`
`-SO2L
`
`CO2H
`
`SO2NHR
`
`SO3H
`
`POOHNH2
`
`POOHOEt
`
`CON HCN
`
`ref 16
`
`Ilydroxy-group
`
`HO....15
`
`OH
`
`NHCOR
`
`NHSO2R
`
`CH0H
`
`NHCONH2
`
`NHCN
`
`ref 16
`
`C-1CN2
`
`ref 16
`
`Catechol
`
`Halogen
`
`N20
`
`HOO
`
`HOX
`
`XNR
`
`Halogen
`
`CF3
`
`CN
`
`NCN
`
`CCN3
`
`ref 16 17
`
`Wallenfels
`Friedrich Rieser
`Edn 1976 15 261
`anorg Chem 1970 379 183 also includes
`von Kohier
`Eichler and
`Salewski
`other possibilities in the sulphur and phosphorus and nitro acid series
`von Wallenfels Chimia 1966 20 303
`
`Thieme Angew Chem Internat
`
`Ertel and
`
`569
`
`

`
`Isosterism and Molecular Modification in Drug Design
`
`Table
`
`continued
`
`Thioet her
`
`CN
`
`/N\
`
`/S\
`
`NCN
`NHCNH2
`
`Ii
`
`II
`
`NHCNH2
`
`Thiourea
`
`Azomethine
`
`Pyridine
`
`CN
`
`CN
`
`\/
`/C\
`
`ref 16
`
`CHNO2
`NHCNH2
`
`II
`
`CN
`
`ref 17
`
`NO9
`
`RNR3
`
`Spacer groups
`
`CH3
`
`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
`in ring opening an
`atom is removed
`conformation similar to the parent molecule may be possible
`
`if
`
`Subsfructure Searching and Bioisosterism
`Although the classical Hansch approach is used largely for optimization within
`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
`compound
`collection and computer
`for doing substructure searches e.g the
`techniques
`
`570
`
`

`
`Thornber
`
`Crossbow suite of programmes.8 For example suppose that random screening
`One may consider bioisosteric replacements for
`has turned up the lead
`the ring the oxygen the polymethylene chain or the amidic moiety and design
`vast number of permutations
`substructure search for compounds of type
`are possible and from these compounds may be available for tests which result
`in new leads which have properties worth exploiting such as perhaps
`
`01OC1LNHCOMe
`
`NHCONHMe
`
`Me
`
`CHCH CHN
`or NR
`SO SO2 Se NCN or NCOR
`n23or4
`
`or alkylincluding forming
`COR CO2R SOR SO2R or CONHR
`AB defined substituents
`
`ring
`
`Examples.The literature of medicinal chemistry is rich in examples of the use
`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 brief discussion of bioisosteres of some indoleamines which has
`some useful
`lessons and Table
`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 Rudinger9
`has reviewed isosteric replacements in the field of peptide chemistry up to 1971
`and some further discussions2 have been published recently
`
`has studied and reviewed the work on bioisosteres
`Indole-amines..-Campaigne2
`and one or two details of the work are instructive
`of 5-hydroxytryptamine
`Whereas
`was inactive as an agonist or antagonist on the rat uterus preparation
`had weak activity
`as an enzyme
`the corresponding tryptophan analogue
`This type of bioisostere
`inhibitor
`for 5-hydroxytryptamine decarboxylase.22
`
`Warr Chemical and Biological Data An Integrated On-Line
`Townsley and
`Approach in Retrieval of Medicinal Chemical Information ed Howe Mime and Pennell
`Symposium Series No 84 American Chemical Society Washington D.C
`1J Rudinger
`in ref Vol II Chapter
`20 Further discussion of peptide backbone replacement
`is found in ref 19 and
`van Wijngaarden in Biological Activity and Chemical Structure ed
`peptide link isostere CH2S has been reported
`Buisman Elsevier Holland 1977
`Carothers Org Chem 1978 43 1623
`Yankeelov Kam-Fook Fok and
`by
`Bosin Medicinal Chemistry Specialist Con
`Campaigne
`Maichel and
`65
`tributions 3rd International Symposium 1972 Butterworths 1973
`Pigini
`Bolle and
`Gianella
`Gualtieri
`Meichiorne
`Angelucci European
`Med Chem 1975 10 29 33
`
`Soudyn and
`Keverling
`
`571
`
`

`
`Isosterism and Molecular Modification in Drug Design
`
`10
`
`5-hydroxytryptamine
`C021-1 5-hydroxytryptophan
`
`CO2H
`
`loses all affinity for the 5-hydroxytryptamine 5-HT receptor but retains it
`part for an enzyme system Similarly in the series of compounds 5-HT 11 12
`and 13 activity has been measured against the rat fundic strip preparation and
`on the enzyme caeruloplasmin.23 Whereas 5-HT is
`substrate for the enzyme
`compound 11 inhibited caeruloplasmins oxidation of 5-HT and noradrenaline
`
`in
`
`Rat Fwzdic Strzp
`
`Intrinsic
`
`activity
`
`PD2
`
`0.96
`
`0.84
`
`4.6
`
`5HT
`
`12
`
`ti.
`
`jj
`
`Compound 12 inhibits only 5-HT oxidation and compound 13 was inactive as
`substrate or an antagonist This would appear to demonstrate that
`for the
`enzyme system the imino grouping at the 1-position of the ring is essential
`On the rat fundic strip however all
`the analogues have full agonist activity
`though with reduced potency
`the 5-HT receptor has
`demonstrating that
`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
`
`Barrass
`
`Goult
`
`Pinder and
`
`Sheds Blochem Pharmacol
`
`1973 22
`
`2891
`
`572
`
`

`
`Thornber
`
`Table
`
`Some recent examples of bioisosterism
`
`Dihydroxyphenylalanine
`
`analogues
`
`xxTo2H H.co2H
`
`Dopa
`
`Mimosine ref 24
`
`HO/Z2
`
`ref 25
`
`Histamine H-2 antagonists
`
`HO12
`
`ref 26
`
`ref 27
`
`IjI
`
`MeCH7SCH2CHNNHMC
`HNN
`
`or NCN ref 28
`
`Me2NCH2
`
`NHMe
`
`NCN or CHNO2 ref 29
`
`Haguchi Mo Pharmacol 1977 13 362
`from Streptomyces species
`natural product
`Shamura
`Inoue
`Tsurvoka
`Ogawa
`Nuda Chem and Pharm Bull Japan 1975
`Watanabe
`Yoshidea and
`23 2669
`26 Synthesized as mimosine analogue
`1977 30 649
`Med Chem 1967 10 961
`Norton and
`Sanders
`Duncan
`Brimblecombe
`Emmett
`Gannelin and
`Durant
`Parsons mt Med Res 1975
`86 See also Suiphurmethylene isosterism in the
`development of metiamide
`Emmett and
`Durant
`Black
`Gannelin
`Gannellin App Chem Biotechnol
`Nature 1974 248 65 and
`1978 28 183
`and Hanbury U.S.P
`128 658
`
`24
`
`25
`
`27
`
`28
`
`26
`
`Harris and
`
`Teitei AustraL
`
`Chem
`
`573
`
`

`
`isosterism and Molecular Modification in Drug Design
`
`Table
`
`continued
`
`Neuroleptics
`
`Anthelmintics
`
`PhS
`
`fl-A drenergic blockers
`
`CH 23X
`
`II
`
`or CHCN ref 30
`
`PhS
`
`NHCO2Me
`
`NHCO2Me
`
`ref 31
`
`PhyX
`
`SorSe ref 32
`
`R_ç--
`
`ref 33
`
`Boehringer Sohn
`U.S.P
`085 216
`Lusi Med Chem 1972 15 982
`Fisher and
`Linn
`Mutzner
`Kulsa
`Milkowski
`Lusi
`Tolman
`Wagner
`Peterson
`Waksmunski
`Med Chem 1978 21 235
`Osteind
`Hanson
`Davis and
`Giese
`
`Dybas
`Eskola
`Bochis
`Mrozik
`Olen
`Egerton and
`
`Costello
`
`Med Chem 1978 21
`
`32
`
`496
`33T Jen
`Wardell
`
`574
`
`Frazee
`Schwartz
`Med Chem 1977 20 1263
`
`Erhard
`
`Kaiser
`
`Colella and
`
`

`
`Thornber
`
`OH
`Cl..LNHBut
`H2N
`
`Cl
`
`Clenbuterol
`
`ref 37
`
`$-Adrenergic stimulants
`
`01-i
`
`1_.NHR
`H01
`
`Me
`
`But
`
`But
`
`Pr
`
`01-1 Adrenaline
`
`CH2OH
`Salbutamol ref 34
`
`NHCONH2
`Carbuterol ref 35
`
`NHSO2Me
`Soterenol
`
`ref 36
`
`NJ..NHPr1 HOX NHPr
`
`ref 38
`
`HZIIL_
`
`ref 39
`
`ref 39
`
`OH
`
`Hk.1ç
`
`ref 40
`
`Jack
`Jack
`
`Lunts and
`Lunts
`
`Ritchie Nature 1968 219 861
`Collin
`ToonJ Med Chem
`Ritchie and
`Press
`
`Corner
`
`Uloth
`
`Dungan and
`
`Hartley
`Hartley
`1970 13 674
`Kaiser Med Chem 1974 17 49
`Larsen
`Gould
`Roth
`Med Chem 1967 10 462
`Lish
`Keck
`Kruger
`Noll and
`1972 22 861
`Machleidt Arzneimittelforsch
`Zenker Med Chem 1978 21 72
`Arnett Wright and
`Williams Canad .1 Chem 1976 54 3377
`Tamada
`Yoshizakj K. Tarimura
`Yabuuchi and
`1976 19 1138
`
`36A
`
`38
`
`30
`
`Nakagawa
`
`Med Chem
`
`575
`
`

`
`Isosterism and Molecular Modification in Drug Design
`
`Table
`
`continued
`
`Vasodilators
`
`-LXR
`XO YCO ref.42
`XS
`
`or
`
`SO2
`
`ref 41
`
`YCO.ref.43
`
`MeO2CJ
`JUL
`
`Me
`
`Me
`
`CO2Me
`
`SO2Me
`
`ref 44
`
`ref 45
`
`Androgens
`
`OAc
`
`SorNCN ref.46
`
`SmithKline Corp U.S.P
`117 128
`Vaughan Williams and
`Polster European
`Drugs 1971 23
`110
`Goldenberg
`Claeys
`Devay
`Wandestrick
`Charlier Chim Ther 1972
`377
`Bauthier and
`Vater Naturwiss 1971 58 578 Drugs of Today 1975 11 154
`Bossert and
`Ciba-Geigy B.P 464 324
`Med Chem 1979 22 119
`W.-H Chiu
`Klein and
`
`Pharmacol 1974 25 241 Unlisted
`
`Descamps
`
`Delaunois
`
`42
`
`576
`
`Wolff
`
`

`
`Thornber
`
`N-N
`
`CO2H or
`
`ref 49
`
`Anti-inflammatory
`
`MeOS%CH2_X
`
`Cl
`
`N-N
`
`ref
`
`CO2H
`
`ref 48
`
`Ornithine decarboxylase inhibitor
`
`H2NCH23CH
`
`NH2
`
`ref 50
`
`NN
`
`Gabergic agents
`
`HO2C.NH2
`HOS NH2
`
`HO Ji
`
`11NH2 H2N
`
`OH
`
`ref 53
`
`ref 51
`
`ref 52
`
`Ellis
`
`Lucas
`
`Witzel
`Holtz
`
`Seiway .1
`
`Med Chem 1969 12 396
`Hudyma
`Juby and
`Shen
`Windholz
`Rosegay
`Matzuk
`Stammer
`Wilson
`Holly
`Willet
`Sarett
`Nuss and
`Amer Chem Soc 1963 85 488
`Risley
`Winter
`Davy
`Drain
`Howes
`Horlington
`Scruton and
`Pharm Pharmaco/ 1971 23 857
`Bey
`Danzin
`van Dorsselaer Mamont
`1978 21 50
`Atkinson
`Giraud
`Rokach
`Share Med Chem 1979 22 99
`Duggan
`Curtis
`Johnston Brain Res 1971 32 69
`Felix and
`Curtis and
`Watkins Nature 1961 191 1010
`
`Jung and
`
`Tardiff
`
`Med Chem
`
`Rooney
`
`McFarlane
`
`Rackham and
`
`577
`
`51
`
`52
`
`

`
`Isosterism and Molecular Modification in Drug Design
`
`Table
`
`continued
`
`Prostaglandin ring system
`
`L_
`
`ref 54
`
`ref 54
`
`ref 55
`
`ref 55
`
`MeN MeY
`
`II
`
`ref 56
`
`ref 57
`
`ref 58
`
`MeN
`
`HNAN
`
`H2NAN_
`Lre
`
`00
`
`.0
`
`Me Me
`
`ref 60
`
`ref 60
`
`ref 61
`
`Soja and
`Soja and
`Whittaker
`
`Shiah Prostaglandins 1978 16 555
`Shiah Med Chem 1978 21 1330
`Armstrong and
`Higgs
`
`Reed Prostaglandins
`
`Bicking
`
`Cragoe
`
`Mandel and
`
`Kuehl Med
`
`Smith
`
`Cragoe
`
`Kuehi and
`
`Mandel
`
`Zoretic
`Zoretic
`Harris
`1978 16 773
`Holtz
`Jones
`Chem 1977 20 1299
`Robb
`Bicking
`Med Chem 1977 20 35
`Hoitz
`Jones
`Med Chem 1977 20 44
`Gould T.-J Lee
`Smith
`Bicking
`Cragoe Med Chem 1977 20 540
`Huisman Rec Tray chim 1977 96 271
`de Koning and
`Eggelte
`
`58
`
`60
`
`and
`
`578
`
`Bicking
`
`Cragoe
`
`Mandel and
`
`Kuehi
`
`Robb
`
`Kuehi
`
`Mandel
`
`

`
`Thornber
`
`HN1N
`
`L%
`
`HN1N
`L%
`
`ref 62
`
`ref 63
`
`ref 63
`
`1LN
`
`RNJL
`
`ref 63
`
`ref.64
`
`ref 65
`
`RNAN/
`
`HO
`
`ref 66
`
`ref 67
`
`ref 68
`
`oa
`
`HO HO
`
`ref 69
`
`ref 70
`
`ref 71
`
`ref 72
`
`Olen and
`
`Kuehi Med
`
`Taylor and
`
`Fried Tetrahedron Letters 1975 1165
`
`579
`
`ea
`
`68
`
`69
`
`72
`
`Org Chem 1977 42 3201
`Branchard and
`Zoretic
`Sirka
`Bruin
`de Koning and
`Huisman Tetrahedron Letters 1975 4599
`Bollinger and
`Muchowski Tetrahedron Letters 1975 2931
`Smith T.-J Lee
`Gould
`Cragoe
`Chem 1977 20 1292
`64 Merck U.S.P 087 435
`Beechams Belgian
`861 956
`66 Beechams Belgian
`861 957
`Miles U.S.P
`27 612
`Pfizer U.S.P
`132 847
`Vlattas and
`Tetrahedron Letters 1974 4459
`Dellavecchja
`Vlattas and
`Tetrahedron Letters 1974 4455
`Dellavecchia
`71 Tanabe Seijaku G.P 229 225
`Hauser and
`Huffman Tetrahedron Letters
`1974 905
`Harrison
`
`

`
`sosterism and Molecular Modification in Drug Design
`
`Table
`
`continued
`
`Prostaglandin ring system continued
`
`Oy
`
`ref 73
`
`ref 74
`
`ref 75
`
`ref 76
`
`Fried Tetrahedron Letters 1974 2733
`Fletcher and
`Harrison
`du Pont de Nemours B.P 428 431
`Fletcher Tetrahedron Letters 1974 2729
`Harrison and
`Med Chem 1975 18 1094
`Bender
`
`580