Medicinal Research Reviews
`
`Volume
`
`Number
`
`OctoberDecember
`
`1986
`
`Contents
`
`the Parkinsonian Syndrome Producing
`The Pharmacology of
`Neurotoxin MPTP 1-Methyl-4-Phenyl-1236-Tetrahydropyridine
`and Structurally Related Compounds
`Markey and
`Schmuff
`
`Compounds Acting on Alpha1
`Agonists and Antagonists
`Sylvester Vizi
`
`and Alpha2_ Adrenoreceptors
`
`Stereochemistry
`
`Source of Problems
`
`in Medicinal Chemistry
`
`Ariºns
`
`Possible Role of Epinephrine
`Rand
`and
`Majewski
`
`in the Development
`
`of Hypertension
`
`Carrier Erythrocytes
`DeLoach
`
`Information for Contributors
`
`Author Index
`
`Volume Contents
`
`389
`
`431
`
`451
`
`467
`
`487
`
`505
`
`507
`
`iii
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 1
`
`

`

`Source of Problems in
`Stereochemistry
`Medicinal Chemistry
`
`Everardus
`
`Ariºns
`
`Institute
`
`of Phannacology
`
`and Toxicology
`University
`EZ NIJMEGEN
`
`of Nijrnegen
`
`Geert Grooteplein Noard 21 6525
`
`The Netherlands
`
`Introduction
`
`Isomeric
`
`Ballast
`
`of Inactive
`Isomers
`III Actions
`IV Drug Metabolism and Stereochemistry
`in Pharrnoltetics
`Stereochemical
`
`Pitfalls
`
`VI Conclusions
`
`and Drug Monitoring
`
`451
`
`453
`
`453
`
`457
`
`462
`
`463
`
`INTRODUCTION
`
`level
`
`racemates
`
`first view On molecular
`common aspect of nature
`Symmetry is
`however asymmetry dominates both in the building materials
`such as anti
`noacids and sugars and in metabolic and regulatory processes in which en
`zymes and specific
`As
`receptors are involved
`the presence
`consequence
`chiral center in drugs and bioactive
`of
`agents in general
`implies large dif
`for the enantiomers both im the activity in the strict
`sense and for
`ferences
`metabolic conversion and pharmacokinetics
`in general
`Structural
`for the biological activity often imply the presence
`requirements
`of one or more chiral centers
`them are marketed
`in the drug Many of
`as
`The enantiomers must particularly
`from the biological point of
`substances.-The neglect
`view be regarded as different
`in
`of stereochemistry
`the development and application
`of drugs and bioactive
`agents in general
`and is
`source of problems in pharmacoki
`leads to serious misconceptions
`netics
`in nature On the
`very common phenomenon
`At first view symmetry is
`molecular
`level however asymmetry dominates as illustrated by the chirality
`of amino acids and sugats and by the stereospecificity
`of enzymatic reactions
`interaction etc This holds true for the whole field of biology
`drug-receptor
`It counts also for various types of messenger molecules
`such as neurotrans
`allosteric modulators
`mitters hormones
`of enzyme activity
`xenobiotic exogenous messenger molecules such as drugs insecticides
`weedkillers These transfer specific
`information chemically coded
`in suitable
`in action is com
`molecular carriers
`into biological objects
`mon Chirality is not
`in those cases and
`requirement
`there are many in which
`in the bioactive molecule
`chiral centre is present
`the enantiomers Un
`are found for the activities of
`great differences
`usually
`the processes involved will be helpful
`in the development
`of
`derstanding of
`more active and selective
`agents and particularly
`in the proper use of ther
`apeutics and of bioactive
`agents in general
`
`as well
`
`as for
`
`and
`
`Stereoselectivity
`but
`
`for bioactivity
`
`Medicinal
`
`Research
`
`1986 by John Wiley
`
`Reviews
`Sons
`
`No
`
`451-466 1986
`
`Vol
`
`Inc
`
`CCC 0198-6325/86/040451-16$04.OO
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 2
`
`

`

`452
`
`ARJENS
`
`basis of
`
`three binding
`
`groups
`
`in the molecule
`
`three-point
`
`Stereospecificity
`
`in solution Once
`be
`
`chromatography
`selective determination
`
`isomers.5569
`
`terated
`
`basis of
`
`No doubt
`the selectivity in action is based on
`chemical complementarity
`between the messenger molecule or pharmacon and its specific
`receptor-site
`the site of binding on the receptor molecule In this complementarity
`besides
`the groups in the molecule which par
`characteristics
`of
`the physicochemical
`their sterical con
`ticipate in the interaction also theft spatial arrangement
`in action can be counted
`for on the
`figuration is essential
`as few as
`interaction.123456
`The isomers do not differ in theft chemical properties
`bound to the specific
`that
`site of action differences
`is stereoselective
`tween the stereoisomers show up
`Separation techniques too are based largely on stereoselective binding of
`one of the isomers to
`proper substrate This holds also true for stereoslective
`and radio-receptor
`such as radio-immuno-
`assays7 and
`analytical methods
`adsorbents
`In this respect also enantio
`via stereoselective
`based on derivatization with an enantiomer of
`chiral
`The two en
`labeled or fluorescent
`reagent opens perspectives.89
`possibly
`antiomers in the racemic drug then form usually easily separable and de
`diastereoisomers
`tectable
`Another possibility is the use of pseudoracemates 11 mixtures of deuter
`and non-deuterated
`and deuterated
`ated
`or ncsn-deuterated
`that deuterated and non-deu
`Since there is plenty of evidence
`often are metabolized in
`even
`compounds
`different
`stereospecific
`This technique is only valid if the deuterium
`way7071 there are restrictions
`stable position free of metabolic attack
`is located
`in
`If more than one center of asymmetry is located
`in one bioactive molecule
`and in other cases of geometric isomers such
`the case
`of diastereoisomers
`chair and boat configurations epimers
`isomerism on
`as cis-trans-isomers
`intramolecular sterical hinderance
`result of differences
`in
`etc as
`between the various groups in the isomers
`the intramolecular relationship
`rule such isomers are more
`these will differ physicochemically
`Therefore as
`easily separated than the enantiomers
`of compounds with
`task
`the latter is still
`asymmetry Separation of
`laborious
`are obtained in
`In organic synthesis normally enantiomers
`proportion
`11 For geometric isomers this proportion depends on the synthetic
`dure Products of biological origin such as hormones
`antibiotics
`form Largely for economic
`rule are obtained in stereospecific
`reasons syn
`killers and in general in
`weed
`such as drugs insecticides
`thetic products
`
`single
`
`center of
`
`proce
`etc as
`
`E.J ARIENS was born on January 29 1918 at Wijk bij Duurstede The Netherlands
`and medicine
`In 1950 he obtained
`of doctor
`the university of Utrecht
`the degree
`sciences M.D. Dr Ariens was promoted
`chemistry Ph.D and of doctor
`and director
`the University
`of Nijmegen His many publications
`of the Department of Pharmacology
`the mechanism of action of biologically
`active compounds
`chemical structure and biological
`and application
`theory More
`he has studied drug design the
`development
`are Book Molecular Pharmacology
`two
`of toxicity His major
`avoidance
`of drugs the
`publications
`Introduction
`on Drug Design Textbook
`volumes and
`series of 10 volumes
`in Dutch 1973 English German Italian Spanish
`and Japanese
`of drugs 1983
`and biological
`
`chemistry
`
`at
`
`concern
`
`and receptor
`
`appeared
`
`in medical
`
`at
`
`activity
`
`recently
`
`rational
`
`appeared
`
`Stereochemistry
`
`activity
`
`He studied
`
`in sciences
`
`in 1954 to professor
`
`to general
`
`toxicology
`
`Indonesian
`
`in press Recently
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 3
`
`

`

`STEREOCHEMISTRY
`
`PROBLEMS
`
`453
`
`dustrial products usually are marketed
`as physicians and in certain cases even
`the producers
`or unaware apply mixtures of compounds
`just one
`is involved.2
`compound
`
`as racemic mixtures The users such
`too often unknowingly
`in the supposition
`
`stereoisomers
`
`that
`
`ISOMERIC BALLAST
`
`In case
`the components in the
`in action only one of
`of stereoselectivity
`mixture the racemate is truly active The biologically more active isomer
`isomer
`the distomer
`This is so
`termed the eutomer
`the less or
`inactive
`of their -d- and -1- or
`-R- and -5- configuration
`but with regard to
`regardless
`particular biological action The iegree of stereospecificity
`that
`is the ratio
`the activities
`the enantiomers
`is termed the
`potencies etc- of
`affinities
`The distomerin the mixture should be regarded as an
`to the effect aimed at
`isomeric ballast not contributing
`impurity or
`to the unwanted effects
`however potentially
`contributes
`
`is
`
`the side-effects
`
`It
`and
`
`of
`
`eudismic ratio.246
`
`of
`
`in
`
`toxicity
`In medicine there apparently is not too much concern about carrying along
`with e.g 50 mg of
`action 50 mg of
`second
`the agent with the therapeutic
`although potentially harmful
`agent with no contribution
`to the desired effect
`such as- -adrenergic
`For certain
`types of
`therapeutics
`agents -adrenergic
`and oral anticoaulaitts
`up to 90% of
`the products
`blockers anti-epileptics
`on the market are in fact
`racemic mixtures For antihistaminics anticholin
`this holds true for about 50% while on the whole
`ergics and local anesthetics
`20 to 25% of
`the therapeutics.1 In certain
`it concerns
`cases
`the differences
`are well established.245123415
`the enantiomers
`activity
`In other cases no information is available
`The implications
`mixtures of active and inactive
`isomers become
`clearer
`if one
`
`of
`
`the use of
`considers ap
`the isomeric ballast
`plication of for instance pesticides Neglect of
`the
`risk Its presence
`implies chemical pollution
`isomer constitutes
`inactive
`of man and animalsor
`be it of
`the milieu interne
`the environment
`of
`in
`general Taken into account
`the growing apprehension on chemical pollution
`one has to be well aware of this situation
`The remarkable discrepancy between on one hand the high degree of
`and on the other hand the acceptance
`required for pharmaceuticals
`impurity as long as isomeric ballast
`is involved should be matter of serious
`concern
`One at least might
`of this impurity is harmless
`the presence
`that
`require
`Time is ripe to consider marketing of really pure drugs
`synthesis and separation
`for stereoselective
`Techniques
`anorganic- and biocatalyst
`by means of stereoselective
`are rapidly develop
`
`purity
`of 50%
`
`of enantiomers
`
`ACTIONS OF INACTIVE ISOMERS
`
`If only one of
`the enantiomers the eutomer is resporsible for the desired
`biological e.g therapeutic action there is no reason why not the in this sense
`different way There is whole
`inactive one the distomer
`could be active in
`spectrum of possibilities in this respect many of which have
`been confirmed
`experimentally
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 4
`
`

`

`454
`
`ARIENS
`
`One isomer has the therapeutic
`the other one contributes
`action
`or even is the main source thereof d-Ketamine is
`the side-effects
`hypnotic and analgetic The i-isomer is the main source
`predominantly
`side-effectsY The anorectic
`of unwanted
`action
`of Fenfluramine
`in use now for about
`15 years is located
`racemate
`-enan
`tiomer recently marketed
`as dextrofenfluramine Isomeride This is
`twice as active and has less disturbing
`dizziness thow
`side-effects
`siness and sedation
`reported for the racemate and to be ascribed
`the inactive
`-enantiomer.31
`to the main effect such as the local anesthetic
`Both isomers contribute
`the isomers of prilocaine whil only one
`
`in the
`
`to
`
`to
`
`action of
`
`contributes
`
`to the
`
`an additional
`
`action like
`but only
`
`vasoconstrictive
`
`action.tm
`
`side-effect
`
`of
`
`the
`
`hemotoxicity.24
`One of
`the isomers may have
`advantageous
`Both isomers are local anesthetics
`in the case of bupivacaine
`-isomer shows
`one the
`The therapeutically
`non-active isomer counteracts
`active
`
`is diuretic
`
`isomer In the diuretic indacrinone
`therapeutically
`and causes uric acid retention
`acts as an uricosuric It antagonizes
`brought bout by the diuretic isomer This is
`the uric acid retention
`as it looks since the natural proportion 11 between
`not as effective
`rule is far from optimal
`the compounds the isomers in mixture as
`study of various mixtures shows that
`of ld8i is optimaltm
`proportion
`Comparable relations are found for the isomers of the diuretic
`Fig
`acid.27
`The isomers may have oposite effects
`isomer
`the d-isomer
`depressant
`
`tienilic
`
`is
`
`In some barbiturates
`convulsant Fig 2.229
`
`the 1-
`
`BAY K8644
`isomers of 1.4-dihydropyridine
`Another example are the optical
`The
`while the
`calcium entry-blocker
`-4R-enantiomer
`being
`In some cases isomers act as com
`the calcium influ3t.29a
`enantiomer promotes
`petitive antagonists of each other Mutual
`between the enantiom
`interaction
`the isomers to their common sites
`ers occurs Dependent on the affinities
`of
`of action the racemic mixture acts as partial agonist.2 In the narcotic
`acts as an agonist
`the racemate dl as
`as an antagonist
`picenadol
`partial
`for other agents3233 among
`agonist.3 Similar
`are reported
`relationships
`which pheromones34
`and auxine-type plant growth substances.35
`have an affinity to common receptors
`thatthe enantiomers
`In those cases
`pseudo
`the racemate will behave
`but differ in their intrinsic activity
`as
`and in
`depend on the affinities
`The characteristics
`In case
`the individual enantiomers
`racemic mixture
`of
`of
`composed of an agonist and
`antagonist with equal affinities
`competitive
`thereof with the racemate
`only 50% wifi be acti
`at saturation
`the receptors
`
`partial agonist
`
`trinsic
`
`activities
`
`vated.35a.35b.35c
`
`thereof
`
`analgetic
`
`to
`
`The isomers may have advantageous
`of
`the ct-f3-adrenergic
`case
`blocking pseudohybrid-drugs.36
`may be restricted to only one component
`Stereoselectivity
`ological action The
`the 13-blockers is
`blocking action of
`and the local anes
`the non-specific
`stereoselective
`cardiodepressant
`in the mechanisms of
`thetic action is not This indicates
`
`complementary action like in the
`
`in the bi
`
`difference
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 5
`
`

`

`STEREOCHEMISTRY
`
`PROBLEMS
`
`455
`
`CL
`
`HO2C-H2c-o
`
`CH3
`
`Uric
`
`acid
`
`mg/dO
`
`1I
`
`11111
`
`111111
`
`10140
`
`10180
`
`10/0
`
`10/10
`
`10/20
`
`lIT
`
`DA.M.I
`
`RM
`
`-3
`
`Figure
`
`PM
`
`humans AM
`SD of healthy
`in plasma uric add concentration
`Change
`vrith the diuretic indacrinone The dose is composed
`17 at day
`of daily treatment
`isomer ratios ranging from 10/0
`et al Clin Pharrnacol
`10/80 mg/mg Tobert
`various
`Thei 293441981 10/10 still causes
`uric add retention
`The ntio 10/80
`action
`
`to
`
`results in
`
`clear uricosuric
`
`18
`
`of
`
`action involved.3738
`
`Then the ations concerned
`can be separated by
`If the eudismic ratio for one e.g the
`suitable molecular manipulation
`for other
`clearly differs or even is inverse
`to that
`action
`therapeutic
`different mechanisms of
`this too indicates
`components in the acti
`action In the last case
`
`the actions
`
`can be separated by separation of
`
`the isomers
`
`ci
`
`depressant
`
`convulsant
`
`RS
`
`convulsant
`
`antagonizes
`
`5-13-dimethylbutyl-5-ethyl
`
`barbituric
`
`add DMBB
`
`and
`of depressant
`Figure
`Stereospedfldty
`Rev Phannacol ToxicoL 21 83 1981 In general
`and
`in the action
`convulsive
`
`component
`
`convulsive
`
`action
`
`for barbiturates
`
`of brbiwrates
`
`Ho Ann
`predominantly depressant
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 6
`
`

`

`456
`
`ARJENs
`
`s_N OCH CHCH NHC--C-1
`
`CH
`
`OH
`
`CH3
`
`S-enantiomer
`
`R-enantiomer
`
`Tirnolol
`
`L-714
`
`465
`
`f3 rl3radrenergic
`blockade
`
`reduction
`
`intra-
`
`ocular
`
`pressure
`
`strong
`
`strong
`
`very weak
`
`slightly less
`
`strong
`
`Figure 2A Richards
`
`et al Br
`
`Clin Pharmacol 1985 20 459
`
`The f3-adrenergic
`effect
`in those cases
`
`-Sotalol
`
`blocking action must be considered as an undesired side-
`in which other components
`in the action
`are exploited
`and the
`both the
`-isomer of sotalol have
`for example
`therapeutically
`class III anti-arrhythmic action while the -adrenergic
`blocking acti on is
`-isomer Theief ore
`is to be preferred
`practically restricted to the
`when the thug is to be used as
`com
`class III anti-arrhythmic agent.38
`the S-isomer which with its R-isomer
`parable reasoning holds true for Timolol
`has in common
`the intra-ocular
`reduction of
`pressure but
`is by far more
`for the treatment
`of
`glaucoma
`the risky
`
`potent as
`-adrenergic
`the R-isomer of Timolol
`
`blocker Therefore
`
`is preferable
`
`since it
`
`is practically free of
`
`adrenergic blocking action35t
`
`fig
`
`The most common situation
`in which one of
`the enantiomers
`is that
`is clearly active while the other one is only poorly active One has to
`take
`into consideration that
`of the enantiomers
`incomplete separation
`counts for the distomer
`
`particularly
`
`distribution
`
`thereof
`
`in
`
`tissues
`
`concern
`
`the eutomer in the distomeric compound
`Presence
`small fraction of
`of
`shows up as activity
`the latter This will be the larger the higher
`of
`the
`is The differences
`eudismic ratio on the receptor system concerned
`in activity
`if measured in vivo as
`fact may also be due to differences
`matter of
`particularly metabolic conversion and excretion The implications
`first-pass metabolism and
`again can differ for oral stereoselective
`administration which is the case for instance
`for the calcium-chan
`parenteral
`Data
`obtained with isolated
`nel blocker Veraparnil.3Sc3Sdt
`in action in the more strict sense
`stereospecificity
`the terms eutomer and
`The various examples
`given above make clear
`that
`particular bio
`distomer and eudismic ratio can be used only in relation to
`logical action The enantiomer
`is the eutomer with the therapeutic
`that
`action
`of ketamine be the distomer
`for unwanted
`may like in the case
`actionsY
`For indacrinone
`the eutomer for the diuretic acfion
`action.26 For certain barbiturates the eutomer
`for the depressant
`action and vice versa29 Fig
`
`uricosuric
`
`action is the distomer
`
`for the convulsant
`
`is the distomer
`
`for the
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 7
`
`

`

`STEREOCHEMISTRY
`
`PROBLEMS
`
`Stereoselectivity
`
`in biological action may like in the cases mentioned
`to the drug-receptor
`the pharmacodynamics
`interaction
`
`be related
`
`457
`
`before
`
`of
`
`the
`
`agent
`It may however
`in the rate of metabolic conversion or even
`
`be due as well
`
`and in differences
`
`in
`
`transport
`1115.424344.45.46
`
`tissues
`
`particular
`tween the isomers is possible
`
`in pharmacokinetics
`to differences
`e.g
`in the pathways invo1ved2394
`and storage
`including uptake
`processes
`Also on this level mutual
`interference
`
`in
`be
`
`DRUG METABOLISM AND STEREOCHEMISTRY
`
`biochemical conver
`There are various possibilities for the enantioselective
`is converted by the en
`isomer
`stereoselectivity Only one
`Substrate
`sion
`zyme The second isomer may show an enzyme inhibitory
`action
`Product
`The non-chiral
`substratewith
`pro-chiral centeris con-
`stereoselectivity
`The
`the product
`the possible enantiomers
`to one of
`of
`verted preferentially
`in drug metabolism may be restricted to differences
`enantioselectivity
`and
`stereoselec
`Combination
`rate of conversion
`of
`substrate-product
`one of the possible diastereoiso
`tivity resulting in formation of preferentially
`the isomers to
`inversion of only one of
`mers too is possible
`Enzymatic
`the other enantiomer This can be considered as
`
`preferentially
`
`particular
`
`in the
`
`case substrate-product
`The schemes Ia
`
`stereoselectivity
`and
`
`various
`
`wide variety of
`and
`exemplify the cases
`metabolic conversion of drugs and xeno
`types of enantioselective
`reported in the literatureY12394
`biotics in general has been
`Drug metabolism implies bioactisration and/or bioinactivation
`of bioactive
`agents not only directly has consequences
`for the type of action
`in metabolic con
`and activity
`because of stereoselectivity
`but also indirectly
`version
`
`Thus chirality
`
`in drug metabolism is observed
`compounds
`in regular
`Enantioselectivity
`where methyl group
`is introduced next to the site of enzymatic attack Such
`then interferes with the enzymatic action maybe by sterical hind
`group
`The introduction of such
`erance or otherwise
`group art often
`protective
`prolongs action It usually implies introduction
`applied manipulation
`usually
`clearly differ in action and
`center of asymmetry The isomers usually
`of
`metabolism One isomer may serve as
`for and the other
`as an
`substrate
`for e.g acetyl43-methylcholine with
`the enzyme This is the case
`inhibitor of
`-IR -isomers is 200 The rate
`the
`ratio for the cholinergic
`action
`of
`is about 50% of that
`of hydrolysis by acetylcholinesterase
`-isomer
`for acetylcholine The
`-isomer is hardly hydrolysed
`an inhibitor of the enzyme.4748 For acetyl-a-methylcholine these
`ratios dearly
`differ The position
`the center of asymmetry in the molecules is of impor
`of
`tance
`the
`-isomer of amphetamine
`table
`Dexamphetamine
`-isomer which is
`more potent stimulant
`than levamphetamine the
`more potent blocker of norepinephrine
`re-uptake in the sympathetic nerve
`in its stereoselec
`deamination is species
`dependent
`endings Amphetamine
`in the rabbit and
`in guinea pig and man.47
`action and
`has an antthypertensive
`Only the
`-isomer of a-methyldopa
`which is in-
`is less toxic than the racemate
`to
`Contrary
`cc-methyldopa
`-isomer is decarboxylated and hydroxylated
`in stereoselective
`
`for the
`
`and
`
`in fact acts as
`
`is
`
`tivity
`
`active the
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 8
`
`

`

`458
`
`Scheme
`
`la
`
`ARIENS
`
`PRODUCT-SELECTIVITY
`
`R2
`
`enzvrn
`
`ft
`
`center
`
`prochiral
`of asymmetry
`
`center
`
`diazepam
`
`prochiral
`
`center C3
`
`desmethyldiazepam
`
`dopamine
`
`propiophenone
`
`enzymatic
`
`oxydatioz
`
`eyma
`
`oxydation
`
`doPamine
`hydroxylase
`
`product
`
`one isomer
`
`N-methyloxazepam
`
`oxazepam
`
`norepinephrine
`
`phenyl-n-propylcarbinol
`
`Scheme
`
`lb
`
`SUBSTRATE-$ELECTIVITY
`
`ftR3
`
`nzym
`
`R1
`
`dl
`
`center of asymmetry
`
`d-isomer
`
`product
`
`same config
`
`as 1-isomer
`
`or
`
`non-chiral
`
`eg
`
`R1
`
`dl-acetyl-f3-methylcholine
`
`Ach-esterase
`
`acetyl-13-methylcholine
`
`dI-prilocaine
`
`amidas
`
`-methylchoIine
`acetic add
`
`prilocaine
`
`toluidine
`
`acetic add
`
`l-methyl-I-aminopropyl
`
`thera
`
`the active endproduct The
`way to
`ctSj3R-methylnorepinephrine
`isomer of a-methyldopa
`is not
`serves as
`prodrug the
`-isomer
`peutically active but contributes to the side-effects.47
`The -i- -isomer of deprenyl
`weak MAO-b-inhibitory
`has only
`antide
`action and is therefore
`it is converted to
`ineffective
`pressant
`therapeutically
`-metamphetamine which is converted to
`-amphetamine both con
`tributing strongly to the undesired CNS stimulant side-effect
`The
`-iso
`strong MAO-B inhibitory
`and thus antidepressant
`mer Selegiline has
`-metamphetamine and
`action It
`is converted to
`therapeutic
`weak unwanted CNS-stimulant
`which have only
`
`respectively
`
`phetante
`side-effect49
`
`fig
`Both isomers of prilocaine
`isomer however
`
`is hydrolysed
`
`have
`
`local anesthetic
`
`action only the
`to toluidine the cause of methemoglobin
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 9
`
`

`

`9TEREOCHEMISTRY PROBLEMS
`
`459
`
`5cheme lc
`
`SUBSTRATE- AND PRODUCT-SELECTIVITY
`
`R1
`
`R1
`
`P1
`
`P1
`
`R4
`
`ft
`
`ft P2
`
`P4
`
`ft
`
`ft P3
`
`enzvm P4
`
`ft
`
`ft
`
`P4
`
`P3
`
`dl
`
`dl-a-methyldopamine
`
`P3
`
`P2
`
`dl
`
`P2
`
`P3
`
`ft
`
`ft P3
`PP2
`
`dopamine
`hydroxyi
`
`-e
`
`d-isomer
`
`one diastereomer
`
`2R
`1R25
`
`cz-methyldopamine
`
`ct-methylnorepinephrine
`
`P1
`
`P3
`
`P1
`
`ft2
`
`R3
`
`one isomer
`
`dI-clidanac
`
`enzymatic-
`
`clidanac
`
`chiral
`
`inversibn
`
`center of asymmetry
`center
`
`prochiral
`
`formation an unwanted side-effect
`
`The
`
`-isomer which is not hydro
`
`fig
`introduction of metabolically
`
`of
`
`stabilizing methylgroup
`The methyl-
`
`in fig
`
`absorption
`
`ester
`
`lysed does not cause this side-effect245
`The implications
`of prostaglandines
`in the critical 15-position
`are illustrated
`lipophilicity and thus facilitates
`formation increases
`An interesting situation is that of the non-steroidal
`antiinflammatory agents
`The therapeutically
`iuch as ibuprofen
`isomer
`certain
`is to
`converted metabolically
`in the body to the active one515253
`fig
`good reasons to apply only the eutomer
`since the conversion
`are however
`place only partially and will depend on
`of the distomer
`to the eutomer
`takes
`inversion
`the patient.52 Metabolic chiral
`
`inactive
`
`extent
`
`There still
`
`the condition e.g liver function of
`
`Cholinergic muscarinic activi
`
`ties and
`
`rate of hydrolysis
`
`by acetycholin
`
`estera se of acetyl-
`
`an
`
`acetyl-a-methylcholine
`
`isomers
`
`Table
`
`compound
`
`acetylcholine
`
`acetyl43-methylcholine
`
`acetyl-13-methylcholine
`
`acetyl-a-methylcholine
`
`acetyl-ct-methylcholine
`
`ileum
`
`guinea pig
`
`1.0
`
`1.0
`
`240
`
`28
`
`230
`
`ratio
`
`240
`
`rates of hydr
`ACh
`
`100
`
`100
`
`54
`
`weak inhibition
`
`97
`
`78
`
`number of molecules
`
`equivalent
`
`to molecule of acetylcholine
`
`Beckett Ann N.Y Aced
`
`Sciences
`
`144 675
`
`1967
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 10
`
`

`

`460
`
`ARIENS
`
`STEREOSELECTIVE ACTION AND B1OTOXICATION
`
`DEPRENYL
`
`_cTrc_
`
`Selegiline
`
`strong
`
`MAO-b inhibitor
`
`-I-
`
`weak
`
`oxydative
`
`dealkvlation
`
`methamphetamine
`
`rnethaniphetamine
`
`CNS stimulant
`
`weak
`
`side-effect
`
`strong
`
`amphetamine
`
`amphetamine
`
`anfidepressant
`
`antiparkinson
`
`Figure
`
`inhibitor and
`
`thus antidepressant
`is metabolized
`methamphe
`Sele
`enantiomer
`
`to
`
`SC
`
`action
`
`The
`
`strong Mao-b
`Deprenyl SelegilineR is
`This enantiomei
`however
`active
`is only poorly
`deprenyl
`with an undesired CNS stimulant
`tamine and amphetamine
`giline is metabolized
`the only poorly stimulant
`amphetamines
`side effect 49 G.P Reynolds et aL Br Gin Pharnzacol
`542 1978
`
`to
`
`and therefore
`
`free of the
`
`BIOTOXICATION
`STEREOSELECTIVE
`LOCAL ANESTHETICS
`
`prilocaine
`
`local anesthetic
`
`Sc
`
`quatacaine
`
`local anesthetic
`
`hydrolyzed
`
`not hydrolyzed
`
`not hydrolyzed
`
`HIOH
`
`no methemoglobinemia
`
`no methemoglobinemia
`
`H0-(cid:231)N-CC-C
`
`toluidine
`
`oxidation
`
`ultimate toxon
`
`methemoglobinemia
`
`Figure
`
`sterical
`
`icated
`
`other
`
`Due to pacldng
`by double methylgroup-substitution
`hindrance
`and thus not biotox
`is resistant against
`consequential
`quatacaine
`The partial packing by one methyl group in prilocaine
`the isomers here
`As often
`in similar situations only one of
`isomer is hydrolyzed and thus biotoxicated 24
`1967
`
`of
`
`the amide function
`
`and
`
`the
`
`hydrolysis
`
`results in
`
`center
`
`of asymmetry
`The
`hindered
`is stericaily
`et al Chem Abstr 67 72325
`
`Takada
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 11
`
`

`

`STEREOCHEMISTRY
`
`PROBLEMS
`
`461
`
`STABILIZING MOIETY AND
`INTRODUCTION OF
`MOIETY IN PROSTAGLANDIN
`FACILITATING
`PGE2
`
`/Th---COOH PGE2
`
`91
`15-OH dehydrogenase
`
`prostaglandin
`
`bioinactivation
`
`If
`
`OH
`
`OH
`
`C0OJ
`
`coo
`
`inhibitor gastric secretion
`
`short
`
`action
`
`inactive
`
`if orally administered
`
`PG 155 15-me-E2me
`inhibitor gastric secretion
`
`ester
`
`prolonged
`
`action
`
`active
`
`at oral administration
`
`PG 15R15-me-E2me
`inhibitor gastric secretion
`smooth muscle
`
`ester
`
`spasmogen
`
`OH
`
`HO
`
`active
`
`at oral administration
`
`stabilizing moiety
`
`disposable
`
`facilitating moiety
`
`Figure
`
`Karim
`
`et al Brit Med
`
`143
`
`1973
`
`dcloprofen
`
`reported for ben(cid:224)xaprofen
`
`adds is further
`of antirheumatic
`2-arylpropionic
`didanac and naproxen.5152
`related enzymes such as the
`can differ for various closely
`Stereoselectivity
`on the dis
`esterases and the mixed function oxidases and thus dependent
`and even differ for var
`these enzymes show spedel differences
`tribution of
`and
`ious organs in one spedes.MSS.SSS7 Monoamine
`oxidase
`enzymes which also differ
`but different
`related
`is metabolized preferentially
`phenylethanolamine
`is metabolized by MAO-B
`enantiomer
`
`are closely
`
`in their distribution
`
`by MAO-A whereas the
`
`00
`
`-Ibuprofeæ
`
`Inversion
`
`of
`
`ibuprofen
`
`in humans
`
`Administered S/R-ratio
`
`Excreted SIR-ratio
`
`S-
`R-
`
`Racemic
`
`95
`694
`50
`
`50
`
`95
`8020
`30
`
`70
`
`Figure
`
`Adapted
`
`from Kaiser
`
`et al 51
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 12
`
`

`

`462
`
`AIUENS
`
`Stereochemical
`
`aspects
`
`ratios
`
`propranolol
`
`in pharmacokinetics
`in man and
`dog 5569
`
`after
`
`oral doses of pseudoracemic
`
`Table
`
`oral bioavailabiity
`
`in urine
`
`unchanged
`
`drug
`
`glucuronides
`
`side chain
`
`oxidation
`
`products
`
`ring oxidation
`
`products
`
`dog
`
`0.53
`
`0.52
`
`3.50
`
`0.47
`
`1.18
`
`man
`
`1.4-4
`
`1.50
`
`1.76
`
`1.45
`
`0.59
`
`The ratios Mao-aMao-b
`
`related
`
`inhibitory
`
`it is
`
`different
`
`often
`
`IC50 values differ for the enantiomers
`inhibitory
`and for
`they are 120 for
`75 for
`For deprenyl
`425a compound
`and 0.5 for .73 For
`to deprenyl 8.8 for
`arniflamine
`the
`enantiomer
`is 500 for the
`ratio KIM.AO-AIMAO-B
`Taken into account
`the differences
`in the various pharmacokinetic param
`initially 11 changes with
`the enantiomers
`the proportion thereof
`the time This holds true for the concentration of the drug as well
`as that
`The enanti(cid:243)mers
`the various metabolites
`even may generate
`spectrum of metabolites.5559606 After application
`of drugs as racemates
`the drug and its metabolites excreted in the urine are optically active
`The stereoselective
`metabolic conversions and possibly
`distribution
`pro
`in the driginal 11 proportion of the enantiomers
`cesses
`resulted
`in
`change
`So for instance application
`to dogs and
`of propranolol as
`psuedoracemate
`man results in clear changes
`in the original 11 ratio of
`the racemate
`in the
`5569 This also illus
`processing as summarized in table
`pharmacokinetic
`for stereospeciflc metabolism No doubt also in plasma
`differences
`species
`from
`the time-plasmaconcentration
`these proportions dearly differ
`curves
`representing the elimination of
`from plasma one may expect
`more labile en
`to the elimination of
`related
`the metabolically
`part
`to the more
`followed by more shallow part
`related predominantly
`stable enantiomer
`If the role of stereoselectivity
`is neglected computerised
`curve fitting will lead to good evidence for an interesting multicompartment
`system with an intriguing
`constants The investigator
`set of pharmacokinetic
`not only fooled himself and his readers but even
`the computer
`
`eters of
`
`of
`
`trates
`
`steeper
`antiomer
`
`Itt
`
`racemate
`
`STEREOCHEMICAL PITFALLS IN PHARMOKINETICS AND
`DRUG MONITORING
`
`Taken into account
`of enan
`in chemical properties
`the lath of difference
`and receptor-binding
`tiomers in solution with the exception of
`inimuno-
`assays and chiral derivatization89 the analytical methods used in the study
`between them The con
`rule do not differentiate
`of pharmacokinetics
`as
`11 of
`measured in fact
`centrations
`original compound and of
`Remarkable
`is the neglectance
`
`concern mixtures not necessarily
`the various metabolites
`
`the
`
`of stereochemical
`
`implications
`
`in clinical
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 13
`
`

`

`STEREOCHEMISTRY
`
`PROBLEMS
`
`463
`
`It
`
`four
`
`is paid to the inherent compli
`
`pharmacology where hardly any attention
`in pharmacokinetics
`cations
`two and even
`is more the rule than the exception that mixtures of
`was
`as if just one compound
`different compounds the isomers
`are treated
`Not withstanding
`the overwhelming abundance of
`involved.62.L6SS(cid:244).(cid:243)7.(cid:243)8
`that different
`isomers usually differ in action they often
`and at different
`rates Also the
`along different
`pathways
`and storage in granula etc are stereoselective
`transport binding to proteins
`and genetic differ
`The condition for instance
`liver function of
`the patient
`ences also count The implications
`of stereochemistry
`for pharmacokinetics
`have
`too for thefapeutic monitoring of patients
`treated with
`consequences
`racemic drugs Conclusions based on the relationship between the dose reg
`imen and the systemic concentration of what
`regarded as the
`is erroneously
`active agent and on the relation thereof with the therapeutic
`therapeutically
`are misleading and possibly risky
`response
`The flow of racemic drugs to the market
`is abundant Of the chiral products
`introduced in 1984 and 1985 if semisynthetic
`such as penicillins
`products
`are left out about 50% are racemates Note
`cephalosporins and polypeptides
`worthy is the frequency with which methyl grpups located
`close to vulnerable
`in the molecule discussed before are the basis for the asymmetry
`positions
`One wonders how much is known about
`various products concerning
`these
`and pharmacodynamics
`including toxi
`
`evidence
`
`for the fact
`
`are metabolized
`
`the differences
`
`in pharmacokinetics
`
`It
`
`drug even
`
`to eliminate
`
`the enantiomers
`cology of
`is amazing how the authorities
`responsible for the acceptance
`registra
`of 50% and more as long
`tion of drugs in various countries
`accept
`impurities
`isomeric ballast They never will accept 50% of
`as it concerns
`in
`byproduct
`if it is considered without proof safe The fact
`that
`it is not easy
`the impurity hardly will count The authorities
`go further
`even
`date on th racemic drugs accepted by them
`They require
`pharmacokinetic
`waste of time and money and
`token of incompetence In those cases
`are replaced in the future by the pure agents the active en
`the racemates
`repeat of preclinical and clinical hives
`of complete
`antiomers
`requirement
`tigation including toxicology thereof would underline the lack of
`in
`in the field
`the implications
`of stereochemistry
`of drug development
`
`that
`
`insight
`and
`
`application
`
`CONCLUSION
`
`The presumption
`enantiomers will behave
`
`that
`
`mixture of
`
`chemicals such as two
`two different
`is involved is not
`tenable In
`as if only one agent
`of the relationship between the dose and
`forward empirical
`analysis
`straight
`and in general
`the therapeutic
`for practical
`the therapeutic
`effect
`efficacy
`studies how
`reasons stereoselectivity may be neglected In pharmacokinetic
`the drug applied and of
`ever where concentrations
`its various metabolites
`of
`one has no right to talk about concentrations
`are measured
`agent and its various metabolites without
`antiomers if
`racemic mixture is involved
`
`differentiating
`
`of the active
`between the en
`
`In the study of bioactive
`
`agents it is preferable
`
`if not
`
`requisite to use pure
`
`DR. REDDY’S LABS., INC. EX. 1061 PAGE 14
`
`

`

`464
`
`ARIENS
`
`that
`
`often
`
`agents compounds with as little impurity as possible Mixtures of compounds
`if one wants
`may be an object of study particularly
`to gain information
`between the compounds
`the interaction
`in the mixture The use of mixtures
`of compounds without
`In those cases
`of it is reprehensible
`being aware
`wh