WILSON AND GISVOLDS
`Textbook of Organic Medicinal
`and Pharmaceutical Chemistry
`
`Ninth Edition
`
`EDITED BY
`
`Jaime
`
`Delgado Ph.D
`Division of Medicinal Chemistry College of Pharmacy
`University of Texas at Austin Austin Texas
`AND
`
`William
`
`Remers Ph.D
`Department of Pharmaceutical Sciences College of Pharmacy
`University of Arizona Tucson Arizona
`
`17 Contributors
`
`Lippincott Company Philadphia
`New York
`London
`
`Hagerstown
`
`Breckenridge Exhibit 1024
`Breckenridge v. Research Corporation Technologies, Inc.
`
`

`
`Production Manager
`Acquisitions Editor
`
`Janet Greenwood
`
`Lisa McAllister
`
`Manuscript
`
`Editor Marguerite Hague
`Production
`Till
`Inc
`Compositor Science Typographers Inc
`The Murray Printing Company
`Printer/Binder
`
`Till
`
`Ninth Edition
`
`Copyright
`
`Copyright
`
`Copyright
`
`Alt
`
`1991 by
`Lippincott Company
`1982 by
`Lippincoft Company
`1977 1971 1966
`1962 1956 by
`1954 by
`Lippincott Company
`Copyright
`No part of
`lights reserved
`this book may be used
`in any manner whatsoever
`reproduced
`or
`embodied in critical
`permission except
`and reviews Printed
`for brief quotations
`articles
`America For
`information write
`Lippincotf Company East Washington
`
`Lippincott Company
`
`Square
`
`Philadelphia
`
`in
`
`without written
`
`the United States
`of
`19105
`
`Pennsylvania
`
`654321
`
`Library of Congress Cataloging in Publication Data
`
`Wilson and Gisvolds textbook
`
`chemistry
`Remers
`
`ot organic medicinal and pharmaceutical
`9th ed
`edited by Jaime
`and William
`17 contributors
`cm
`Includes bibliographical
`
`Delgado
`
`references
`
`Includes
`index
`ISBN 0-397-50877-8
`Chemistry Pharmaceutical
`Chemistry Organic
`Charles Owens 1911
`II Gisvold Ole 1904
`William Alan 1932
`IV Remers William
`Jaime
`Title. Textbook
`of organic medicinal
`and pharmaceutical
`
`Wilson
`III Delgado
`
`chemistry
`
`Chemistry Pharmaceutical
`RS403T43
`1991
`615 19dc2O
`DNLM/DLC
`for Library of Congress
`
`OV 744 W754
`
`90-13652
`
`CIP
`
`changes
`
`insert
`
`The authors and publisher have exerted every effort
`and dosage
`to ensure that drug selection
`forth in this text are
`in accord with current
`recommendations and practice
`the time of publication However
`in view of ongoing research
`at
`regulations and the constant
`in government
`flow of information
`relating to drug therapy and drug reactions
`the reader
`is urged to check
`for each drug for any change
`and dosage
`and for
`the package
`in indications
`added warnings
`This is particularly important when the recommended agent
`and precautions
`new or infrequently
`employed drug
`
`set
`
`is
`
`

`
`CHAPTER
`
`Physicochemical Properties
`in Relation to Biologic Action
`
`John
`
`Block
`
`INTRODUCTION
`
`Early drug design started with elucidation of the
`the natural product
`followed by selec
`structure of
`in the molecule The latter was done
`tive changes
`of an
`including the reduction
`for many reasons
`response side effect ob
`undesirable pharmacologic
`taming
`better pharmacokinetic
`response altering
`the drugs metabolism securing
`more plentiful
`less costly supply and producing
`competing prod-
`uct Let us use the morphine alkaloid as an example
`Literally thousands of compounds have been synthe
`sized in an attempt to separate the desired analgesia
`from the
`undesirable addiction
`This
`liability
`in numerous
`research laborato
`tremendous
`effort
`ries over many years and involving many scientists
`better un
`had been minimally successful until
`see
`the opiate receptor
`derstanding of
`developed
`Chap
`In other examples there has been good success at
`this empirical approach Alteration of
`the cocaine
`local anes
`structure has led to the very successful
`thetics that lack cocaines undesirable central effects
`see Chap 15 In contrast with this success story
`there have been no significant commercial
`synthetic
`replacements for digitalis or colchicine
`Synthetic medicinal chemistry as
`discipline be-
`came more intense in the 1900s but many of
`the
`so-called principal compounds still were based on
`fortuitous observation or an un
`natural product
`suspected chemical reaction The phenothiazines see
`Chap
`were first synthesized
`as antihistamines
`but
`careful pharmacologic evaluation led to their
`revolution
`use as major tranquilizing agents that
`ized the care of the severely mentally ill patient The
`see Chap
`originated from an
`benzodiazepines
`unexpected ring enlargement and resulted in
`very
`important group of central nervous system relax
`ants
`Economic factors have stimulated the type of sci
`focused
`required to carry out
`entific investigations
`
`Modern drug design as compared with Lets make
`change on an existing compound or synthesize
`and see what happens
`new structure
`is
`fairly
`is based on
`in its infancy It
`recent discipline still
`modern chemical
`techniques utilizing recent knowl-
`edge of disease mechanisms and receptor properties
`good understanding of how the drug is trans-
`ported into the body distributed throughout
`the
`body compartments metabolically altered by the
`liver and other organs and excreted from the pa-
`is required along with the structural charac-
`tient
`teristics of the receptor Acidbase chemistry is uti-
`lized to aid in formulation and biodistribution Those
`structural attributes and substituent patterns
`re-
`sponsible for optimum pharmacologic activity can be
`predicted many times by statistical
`such
`techniques
`as regression analysis Conformational analysis per-
`the drugs
`mits the medicinal
`chemist
`to predict
`three-dimensional shape that
`is seen by the recep-
`tor With the isolation and structural determination
`receptors and the availability of computer
`of specific
`software that
`can estimate the three-dimensional
`the receptor
`is possible to design
`show an optimum fit
`to the
`that will
`
`of
`
`shape
`molecules
`
`it
`
`receptor
`
`HISTORY
`
`drugs were extracted from plant sources to
`Initially
`obtain agents such as digitalis quinine and mor-
`phine medicinal agents that are still
`in use today
`Specific plants are selected by the chemist because
`the crude preparations were being used for treat-
`ment of medical conditions by the local population
`where the plant grew
`
`

`
`P/-I YSICOC/-f EM/CAL PROPERTIES IN RELATION TO BIOLOGICAL
`
`ACTION
`
`new drug development
`It has become increasingly
`new drug that will be approved
`costly to develop
`Food and Drug Administration FDA
`by the
`At one time safety was the main criterion for FDA
`is an es
`approval Today demonstration of efficacy
`along with safety considera
`sential
`requirement
`tions This has led to
`increased basic research on
`the disease process for which
`drug treatment
`is
`sought
`mathematically modeling the pharma-
`cokinetics of the drugs distribution
`elucidation
`the biochemistry of
`of
`the pharmacologic
`response
`from the drug
`learning the metabolic fate of the
`drug
`defining those specific structural character-
`istics of the drug responsible for the desired phar-
`where possible visualiz-
`macologic response and
`ing the structural
`the receptor
`characteristics
`of
`Although the number of new compounds introduced
`annually has decreased
`from earlier years the prod
`ucts now coming into use are showing dramatic
`effects in the treatment of disease More impor-
`tantly because of the intensive background investi-
`
`Oral
`
`__________________
`
`intramuscuf1
`or
`Subcutaneous
`Injection
`
`gation that has
`todays new
`led to the design of
`of the drugs mecha
`better understanding
`agents
`nism of action is known Indeed this is an exciting
`time to practice pharmacy
`
`OVERVIEW
`
`chemical molecule Following introduc
`drug is
`drug must pass through many
`tion into the body
`barriers survive alternate sites of attachment
`and
`storage and avoid significant metabolic destruction
`reaches
`before it
`the site of action usually
`recep
`cell Fig 2-1 At the receptor
`tor on or
`in
`the
`following equilibrium usually holds
`
`Drug
`
`Receptor
`
`DrugReceptor Complex
`
`Pharmacologic Response
`Rx 2-1
`
`Gastrointest1na
`Tract
`
`Tissue
`
`Depots
`
`Intravenous
`Injection
`_____________
`
`for
`Desired
`eptors
`Effects
`
`DRUG
`
`DRUG
`
`DRUG
`
`DRUG-DRUG METABOLITES
`
`DRUG
`
`Serum Albumin
`
`SYSTEMIC CIRCULA11ON
`
`DRUG
`
`DRUG METABOLITES
`
`DRUG-DRUG
`
`PIETABOLITES
`
`DRUG-DRUG METABOLITES
`
`ii.ipi
`
`Intestinal
`
`jract
`
`_____________
`
`Feces
`
`xcretion
`
`of DRUG-DRUG
`
`Liver
`
`site of most drug metabolil
`
`bile
`
`duct
`
`Kidneyl
`
`Drug must pass
`
`through membranes
`
`Drug administered directly into systemic circulation
`
`FIG 2-I Summary of drug distribution Solid bars Drug must pass through membranes
`systemic circulation
`
`Broken lines Drug administered
`
`directly into
`
`DRUG-DRUG METABOLITES
`
`Receptl
`for
`Undesired
`
`fects
`
`

`
`The ideal drug molecule will show favorable-binding
`to the receptor such that the equilib-
`characteristics
`rium lies to the right At the same time the drug will
`be expected to dissociate from the receptor and reen-
`ter systemic circulation to be excreted The major
`exceptions include the alkylating agents used in can-
`cer chemotherapy see Chap
`and
`few inhibitors
`see Chap 12
`the enzyme acetyicholinesterase
`of
`Both of
`these subclasses
`of pharmacologic
`agents
`form covalent bonds with the receptor
`In these
`cases the cell must destroy the receptor or as with
`the cell would be replaced
`the alkylating agents
`In other words the usual
`normal cell
`ideally with
`use of drugs in medical
`treatment call for the drugs
`finite period Then if
`to last
`for only
`is to
`effect
`be repeated the drug will be administered again if
`the patient does not tolerate the drug well
`is even
`more important
`that the agent dissociate from the
`receptor and be excreted from the body
`
`it
`
`it
`
`DRUG DISTRIBUTION
`
`ORAL ADMINISTRATION
`
`An examination of the obstacle
`
`course see Fig 2-1
`better understanding of
`faced by the drug will give
`what
`is involved in developing
`commercially feasi-
`ble product Assume that
`the drug is administered
`orally The drug must go into solution for it
`to pass
`through the gastrointestinal mucosa Even drugs
`administered as true solutions may not remain in
`the acidic stomach and then
`solution as they enter
`tract This will be
`pass into the alkaline intestinal
`in the discussion on acidbase
`further
`explained
`chemistry The ability of
`the drug to dissolve is
`factors including its chemical
`governed by several
`structure variation in particle size and particle sur-
`face area nature of the crystal form type of coating
`and type of tablet matrix By varying the formula
`tion containing the drug and physical characteristics
`is possible to have
`the drug it
`of
`drug dissolve
`quickly or slowly the latter being the situation for
`products An example
`many of the sustained-action
`is orally administered sodium phenytoin for which
`variation of both the crystal
`form and tablet adju-
`vants can significantly alter
`the bioavailability of
`this drug which is widely used in the treatment of
`epilepsy
`Chemical modification is also used to
`limited
`extent For example sulfasalazine used in the treat-
`ment of ulcerative colitis passes through
`substan-
`tract before being me-
`the intestinal
`tial portion of
`tabolized to sulfapyridine and 5-aminosalicylic acid
`The latter compound is believed to be the active
`agent for the treatment of ulcerative colitis
`
`DRUG DISTRIBUTION
`
`HOC
`
`HO
`
`SuIfasaazne
`
`it
`
`if
`
`Any compound passing through the gastrointesti
`nal tract will encounter
`the many and various diges
`in theory can degrade the drug
`tive enzymes that
`molecule In practice when
`new drug entity is
`under investigation it will probably be dropped from
`is found unable to survive
`further consideration
`tract An exception would be
`in the intestinal
`drug
`for which there is no other effective product avail-
`able or one that provides more effective treatment
`over existing products and can be administered by
`an alternate route usually parenteral
`these same digestive enzymes can be
`In contrast
`used to advantage Chioramphenicol
`is water-soluble
`enough that it comes in contact with the taste recep
`tors on the tongue producing an unpalatable bitter-
`ness To mask this intense bitter
`taste the palmitic
`the chloram
`acid moiety is added as an ester of
`phenicols primary alcohol This reduces the parent
`drugs water solubility so much that
`it can be for-
`mulated as
`suspension that passes over the bitter
`taste receptors on the tongue Once in the intestinal
`tract the ester linkage is hydrolyzed by the digestive
`esterases to the active antibiotic
`chioramphenicol
`and the very common dietary fatty acid palmitic
`acid
`
`NHCOCHCI2
`
`O2NHHCH2OR
`OH
`
`Chioramphenicol
`
`Chioramphenvo
`
`Palmitate
`
`II
`
`CCH214CH3
`
`and chioramphenicol
`Sulfasalazine
`palmitate are
`examples of prodrugs Most prodrugs are corn-
`pounds that are inactive in their native form but
`are easily metabolized to the active agent Sulfasala
`zine and chioramphenicol
`palmitate are examples of
`prodrugs that are cleaved to smaller compounds
`one
`of which will be the active drug Others are metabolic
`form An example of this
`to the active
`precursors
`simple naph
`type of prodrug is menadione
`thoquinone which
`converted
`in the liver
`to
`is
`vitamin K220
`
`

`
`PHYSICOCHEMICAL
`
`PROPERTIES IN RELATION TO BIOLOGICAL ACTION
`
`EIIIIIII1
`
`Menadione
`
`CH3
`
`Vitamin K220
`
`CH3
`
`CH3
`
`CH3
`
`OH3
`
`Occasionally
`the prodrug approach is used to en-
`hance
`the absorption
`of
`drug that
`is poorly ab-
`sorbed from the gastrointestinal
`tract Enalapril
`is
`the ethyl ester of enalaprilic acid an active inhibitor
`of angiotensin-converting enzyme The ester pro-
`drug is much more readily absorbed orally than the
`carboxylic acid
`
`Most drug molecules are too large to enter
`by an active transport mechanism through the pas
`sages On the other hand some drugs do resemble
`normal metabolic precursor
`intermediate and
`or
`they can be actively transported into the cell
`
`the cell
`
`PARENTERAL ADMINISTRATION
`
`Enatapril
`
`C2H5
`
`OH
`
`rj
`Enalaprilic Acid
`
`Unless the drug is intended to act
`locally in the
`it will have to pass through
`gastrointestinal
`tract
`the gastrointestinal mucosa barrier into the venous
`circulation to reach the receptor site This involves
`distribution or partitioning between the aqueous
`environment of
`the gastrointestinal
`the lipid
`tract
`bilayer cell membrane of
`the mucosa cells possibly
`the aqueous interior of
`the mucosa cells the lipid
`bilayer membranes
`on the venous
`side of the gas-
`tract and the aqueous environment of
`trointestinal
`venous circulation Some very lipid-soluble drugs
`may follow the route of dietary lipids by becoming
`the mixed micelles passing through the
`part of
`mucosa cells into the thoracic duct of the lymphatic
`system and then into the venous circulation
`The drugs passage through the mucosa cells can
`be passive or active As will be discussed later in this
`chapter the lipid membranes are very complex with
`highly ordered structure Part of this membrane is
`series of channels or tunnels that form disappear
`and reform There are receptors that move com-
`pounds into the cell by
`process called pinocytosis
`
`Many times there will be therapeutic
`advantages to
`bypass the intestinal barrier by using parenteral
`injectable dosage forms for example because of
`illness the patient cannot
`tolerate or is incapable of
`accepting drugs orally Some drugs are so rapidly
`and completely metabolized to inactive products
`in
`the liver
`first-pass effect that oral administration is
`that does not mean that
`precluded But
`the drug
`administered by injection is not confronted by obsta
`des see Fig 2-1 Intravenous administration places
`the drug directly into the circulatory system from
`which it will be rapidly distributed throughout
`the
`body including tissue depots and the liver
`in which
`most biotransformations occur
`in addition to the
`receptors
`It
`
`is possible to inject
`the drug directly into spe
`the body Intraspinal and
`cific organs or areas of
`intracerebral
`routes will place the drug directly into
`the spinal
`fluid or brain respectively
`bypassing
`specialized tissue the bloodbrain barrier which
`protects the brain from exposure to diverse metabo
`lites and chemicals The bloodbrain barrier is corn
`posed of membranes of tightly joined epithelial cells
`lining the cerebral capillaries The net result is that
`the brain is not exposed
`to the same variety of
`compounds that other organs are Local anesthetics
`are examples of administration of
`drug directly on
`the desired nerve
`form of anes
`spinal block is
`thesia performed by injecting
`local anesthetic di-
`rectly into the spinal cord at
`location to
`block transmission along specific neurons
`
`specific
`
`

`
`or
`
`Many of the injections
`patient will experience in
`lifetime will be subcutaneous
`intramuscular
`These parenteral routes produce
`in the tis
`depot
`sues see Fig 2.1 from which the drug must reach
`lymph to produce systematic
`the blood or
`effects
`Once in systemic circulation the drug will undergo
`the same distributive phenomena as orally and in-
`administered agents
`the
`In general
`travenously
`same factors that control
`the drugs passage through
`the gastrointestinal mucosa will also determine the
`rate of movement out of the tissue depot
`The prodrug approach also can be used to alter
`the solubility characteristics which in turn can
`in possible dosage forms The
`increase the flexibility
`solubility of methylprednisolone can be altered from
`essentially water-insoluble methyiprednisolone ac-
`slightly water-insoluble methylpred-
`etate
`to
`to water-soluble methylprednisolone
`nisolone
`sodium succinate The water-soluble
`sodium succi-
`nate salt is used in oral intravenous and intramus-
`forms Methyiprednisolone
`dosage
`cular
`is
`itself
`normally found in tablets The acetate ester is found
`in topical ointments and sterile aqueous suspensions
`for intramuscular
`injection Both the succinate and
`acetate esters are hydrolyzed to the active methyl-
`by the patients own systemic hydro-
`prednisolone
`lytic enzymes
`
`CH OR
`
`OH3
`
`--OH
`
`HO
`
`CH3
`
`OH3
`
`Methylprednisolone
`
`Ester Available
`
`Methyiprednisolone Acetate
`
`COCH3
`
`Salt Available
`Methyiprednisolone Sodium Succinate
`
`COCH2CH2OOONa
`
`PROTEIN BINDING
`
`Once the drug enters the systemic circulation see
`Fig 2-1 it can undergo several events
`It may stay
`in solution but many drugs will be bound to the
`serum proteins usually albumin Thus
`new equi-
`librium must be considered Depending on the equi-
`librium constant
`the drug can remain in systemic
`circulation bound to albumin for
`considerable pe-
`nod and be unavailable to the sites of biotransfor-
`mation the pharmacologic
`receptors and excretion
`
`Drug
`
`Albumin
`
`DRUG DISTRIBUTION
`
`Drug-Albumin Complex
`Rx 2-2
`
`The effect of protein binding can have
`profound
`result on the drugs effective solubility biodistribu
`tion half-life in the body and interaction with other
`drug with such poor water solubility that
`drugs
`of the unbound active
`therapeutic concentrations
`drug normally cannot be maintained still
`can be
`very effective agent The albumindrug complex acts
`reservoir by providing concentrations
`as
`of
`free
`re
`drug large enough to cause
`pharmacologic
`
`sponse
`Protein binding may also limit access to certain
`body compartments The placenta is able to block
`to fetal circula
`passage of proteins from maternal
`tion Consequently drugs that normally would be
`to cross the placenta barrier and possibly
`expected
`harm the fetus are retained in the maternal circula
`tion bound to the mothers serum proteins
`Protein binding also can prolong the drugs dura
`tion of action The drugprotein complex is too large
`through the renal glomerular membranes
`to pass
`preventing rapid excretion of the drug Protein bind
`ing limits the amount of drug available forbiotrans
`formation see later and Chap
`and for interaction
`with specific receptor sites For example the try
`suramin remains in the body
`panocide
`in the
`protein-bound form as long as three months The
`maintenance
`dose for this drug is based on weekly
`administration At
`this might seem to be an
`first
`It can be but it also means
`advantage to the patient
`that should the patient have serious adverse
`reac
`tions it will
`length of time
`substantial
`require
`before the concentration
`of drug falls below toxic
`
`levels
`The drugprotein-binding phenomenon
`can lead
`to some interesting drugdrug interactions result-
`ing when one drug displaces another
`from the bind
`ing site on albumin Diverse drugs can displace the
`anticoagulant warfarin from its albumin-binding
`sites This increases the effective concentration
`of
`warfarin at
`the receptor
`leading to an increased
`forma
`prothrombin time increased time for clot
`tion and potential hemorrhage
`
`TISSUE DEPOTS
`
`The drug also can be stored in tissue depots Neutral
`fat constitutes some 20% to 50% of body weight and
`depot of considerable importance The
`constitutes
`more lipophilic the drug is the more likely it will
`concentrate in these pharmacologically
`inert depots
`The short-acting lipophilic barbiturate thiopental
`redis
`into tissue protein
`reportedly disappears
`
`

`
`PHYSICOCHEMICAL
`
`PROPERTIES IN RELATION TO BIOLOGICAL ACTION
`
`tributes into body fat and then slowly diffuses back
`out of
`the tissue depots but
`in concentrations
`too
`low for any pharmacologic
`response Hence only the
`administered thiopental
`is present
`in high
`initially
`enough concentrations
`to combine with its
`tors In general structural changes
`rate series see Chap
`that favor partitioning into
`the lipid
`the duration of
`tissue stores decreases
`action but
`increases central nervous system depres-
`sion Conversely the barbiturates with the slowest
`onset and longest duration of action contain the
`more polar side chains This latter group of barbitu-
`rates both enters and leaves
`the central nervous
`system very slowly as compared with the more
`lipophilic thiopental
`
`in the barbitu-
`
`recep-
`
`DRUG METABOLISM
`
`All substances
`including drugs metabolites and
`nutrients that are in the circulatory system will
`through the liver Most molecules absorbed
`pass
`from the gastrointestinal
`tract will enter
`the portal
`vein and be transported to the liver
`large propor-
`drug will partition or be transported into
`tion of
`the hepatocyte where it may be metabolized
`by
`
`hepatic enzymes to inactive chemicals during the
`trip through the liver by what
`is known as the
`initial
`first-pass effect Over 60% of
`the local anesthetic
`lidocaine is metabolized dur
`antiarrhythmic agent
`ing its initial passage through the liver resulting in
`to administer orally When used
`it being impractical
`is administered intra
`for cardiac arrhythmias it
`venously This rapid metabolism of lidocaine is used
`to advantage when stabilizing
`patient with cardiac
`arrhythmias Should too much lidocaine be adminis
`
`Cl
`
`C2H5
`
`NH
`
`01
`
`OH
`
`II
`
`NH
`
`Lidocaine
`
`OH3
`
`OH
`
`NH
`
`OH3
`
`OH3
`
`Tocainide
`
`Sulindac
`
`CH3SO
`
`Active Sulfide Metabolite
`
`CH3S
`
`Azathioprene
`
`6-Mercaptopurine
`
`10
`
`11
`
`10
`
`11
`
`OH3
`
`OH3
`0H2OH2OH2N HOI
`
`cIIJ1IIIiIJ
`HO0H2OH2N
`
`OH3
`
`HOI
`
`Imipramlne
`
`Desrpramine
`
`CH3
`
`Amitriptyline
`
`OH3
`
`Nortriptyline
`
`Phenacetin
`
`A1 C2H50 A2 CH3CO A3
`R1 HO R2 CH3CO A3
`Acetaminophen
`
`

`
`is
`
`tend to
`tered intravenously
`toxic
`responses will
`abate because of the rapid biotransformation to in-
`An
`the
`active metabolites
`understanding
`of
`metabolic labile site on lidocaine led to the develop-
`ment of the primary amine analogue tocainide In
`contrast with lidocaines
`less than two
`half-life of
`15 hours with
`is about
`hours tocainides
`half-life
`the drug excreted unchanged The develop-
`40% of
`ment of orally active antiarrhythmic
`agents is dis-
`in Chapter 14
`cussed in more detail
`the metabolic
`drug is
`study of
`fate of
`for all new products Many times it
`requirement
`found that
`the metabolites also are active Indeed
`sometimes the metabolite is the pharmacologically
`active molecule These drug metabolites can provide
`the leads for additional
`of potentially
`investigations
`new products Examples of where an inactive parent
`drug is converted to an active metabolite include the
`nonsteroidal anti-inflammatory agent sulindac be-
`ing reduced to the active
`sulfide metabolite the
`immunosuppressant azathioprine being cleaved to
`the purine antimetabolite 6-mercaptopurine and
`purine and pyrimidine antimetabolites and antiviral
`agents being conjugated to their nucleotide form
`Many times both the parent drug and its metabolite
`are active which has led to two commercial prod-
`ucts instead of just one being marketed About 75%
`to 80% of phenacetin now withdrawn from the
`market is converted to acetaminophen
`In the
`see Chap 10
`antidepressant
`series
`tricyclic
`imipramine and amitriptyline are N-demethylated
`to desipramine and nortriptyline respectively All
`four compounds have been marketed in the United
`States The topic of drug metabolism is more fully
`discussed in Chapter
`drugs metabolism can be
`source of
`Although
`frustration for the medicinal chemist pharmacist
`and physician and can lead to inconvenience and
`compliance problems for the patient
`is fortunate
`the body has the ability to metabolize foreign
`that
`molecules xenobiotics Otherwise many of
`these
`substances could remain in the body for years This
`has been
`the complaint
`against certain lipophilic
`chemical pollutants including the once very popu-
`insecticide DDT Alter entering the body these
`lar
`chemicals sit
`in body tissues slowly diffusing out of
`the depots and potentially harming the individual on
`prolonged basis for several years
`
`it
`
`EXCRETION
`
`The main route
`drug and its
`of excretion
`of
`metabolites is through the kidney For some drugs
`
`DRUG DISTRIBUTION
`
`enterohepatic circulation see Fig 2-1 in which the
`the intestinal
`from the liver
`drug reenters
`tract
`can be an important part of
`through the bile duct
`the agents distribution in the body and route of
`excretion The drug or drug metabolite can reenter
`systemic circulation by passing once again through
`the intestinal mucosa
`portion of it also may be
`excreted in the feces Nursing mothers must be
`concerned
`because drugs and their metabolites can
`be excreted in human milk and be ingested by the
`nursing infant Usually the end products
`of drug
`metabolism are very water-soluble relative to the
`parent molecule Obviously drugs that are bound to
`serum protein or show favorable partitioning into
`tissue depots are going to be excreted more slowly
`for the reasons already discussed
`This does not mean that
`those drugs that
`for
`remain in the body for longer periods lower doses
`can be administered or the drug can be taken fewer
`times per day by the patient Several variables deter
`mine dosing regimens of which the affinity of the
`is crucial Reexamine Reaction
`drug for the receptor
`2-1 and Figure 2-1 If the equilibrium does not
`favor
`formation of the drugreceptor
`complex higher and
`usually more frequent doses will have to be adminis
`tered If the partitioning into tissue stores metabolic
`degradation or excretion are favored it will
`take
`more drug and usually more frequent administra
`tion to maintain therapeutic
`concentrations
`the
`at
`receptor
`
`RECEPTOR
`
`With the exception of general anesthetics see Chap
`the working model for
`pharmacologic
`response
`consists of
`drug binding to
`specific receptor
`Many drug receptors actually are used by endoge
`nously produced ligands Cholinergic agents interact
`with the same receptors
`the neurotransmitter
`as
`Synthetic
`bind to the
`acetylcholine
`corticosteroids
`same receptors
`and hydrocortisone
`as cortisone
`Many times receptors for the same ligand will
`be
`found in
`the body
`variety of
`tissues throughout
`The
`see
`nonsteroidal
`anti-inflammatory
`agents
`Chap 17 inhibit
`the prostaglandin-forming enzyme
`which is found in nearly every tis
`cyclooxygenase
`sue This class of drugs has
`long list of side effects
`with many patients complaints Note in Figure 2-1
`that depending on which receptors contain bound
`drug there may be desired or undesired effects This
`is because
`receptors with
`there are
`variety of
`requirements found
`similar structural
`in several
`organs and tissues Thus the nonsteroidal anti
`
`

`
`10
`
`PI-IYSICOCI-IEMICAL
`
`PROPERTIES IN RELATION TO BIOLOGICAL
`
`ACTION
`
`inflammatory drugs combine with the desired cy-
`cloxygenase receptors at the site of the inflammation
`in the gastrointestinal mucosa
`and the receptors
`causing severe discomfort and sometimes ulceration
`One of
`the newer antihistamines
`terfenadine is
`claimed to cause less sedation because it does not
`readily penetrate the bloodbrain barrier The ratio-
`nale is that less of this antihistamine is available for
`the receptors in the central nervous system that are
`responsible for the sedation response characteristic
`In contrast some antihistamines
`of antihistamines
`are used for their central nervous system depressant
`activity which would
`considerable
`imply that
`amount of
`the administered dose is crossing the
`bloodbrain barrier
`relative to binding to the his-
`tamine-1 H1 receptors in the periphery
`is normal
`to think of side effects
`Although it
`as
`undesirable they sometimes can be beneficial and
`lead to new products The successful development of
`oral hypoglycemic agents used in the treatment of
`diabetes began when it was found that certain sul-
`effect see Chap
`fonamides had
`hypoglycemic
`Nevertheless
`real problem in drug therapy is
`patient compliance to take the drug directed Drugs
`that cause serious problems and discomfort tend to
`be avoided by the patient
`
`SUMMARY
`
`One of the goals is to design drugs that will
`interact
`with receptors at specific tissues There are several
`altering the molecule
`ways to do this including
`which in turn can change
`the biodistribution
`the specificity
`for
`the desired receptor
`increasing
`desired pharmacologic
`response while decreasing
`the affinity for undesired receptor producer of side
`effects and
`the still experimental approach of
`the drug to
`monoclonal antibody
`attaching
`that
`will bind to
`specific tissue that is antigenic for the
`antibody Alteration of biodistribution can be done
`by changing the drugs solubility enhancing its abil-
`ity to resist being metabolized usually in the liver
`altering the formulation or physical characteristics
`the drug and changing the route of administra-
`of
`drug molecule can be designed in such
`tion If
`way that
`its binding to the desired receptor
`is en-
`hanced
`to the undesired
`and
`receptor
`relative
`biodistribution remains favorable
`smaller doses of
`the drug can be administered This in turn reduces
`the amount of drug available for binding to those
`receptors responsible for its side effects
`Thus the medicinal chemist
`is confronted with
`bioactive molecule
`several challenges in designing
`is desirable but the
`good fit
`to
`specific
`
`receptor
`
`drug would normally be expected
`to eventually dis
`sociate from the receptor The specificity
`for the
`that side effects would be
`receptor would be such
`minimal The drug would be expected
`to clear
`the
`reasonable time Its rate of metabolic
`body within
`should allow reasonable dosing sched
`degradation
`ules and ideally oral administration Many times
`the drug chosen
`for commercial
`sales has been Se-
`lected from the hundreds of compounds that have
`been screened It usually is
`compromise product
`medical need while demonstrating
`that meets
`good patient acceptance
`
`ACIDBASE PROPERTIES
`
`INTRODUCTION
`
`Most drugs used today can be classified as acids or
`bases As will
`be noted shortly many drugs can
`behave
`as either acids or bases as they begin their
`journey into the patient
`in different dosage forms
`and end
`up in systemic
`circulation
`drug
`acidbase properties can influence greatly its biodis
`tribution and partitioning characteristics
`Over
`the years at
`least
`four major definitions of
`acids or bases have been developed The model com
`monly used in pharmacy and biochemistry was de
`by Lowry and Brönsted In
`veloped
`independently
`their definition an acid is defined as
`proton donor
`and
`proton acceptor Notice that
`base as
`for
`base there is no mention of the hydroxide ion
`
`ACIDCONJUGATE BASE
`
`examples of pharmaceutically impor
`Representative
`tant acidic drugs are listed in Table 2-1 Each acid
`conjugate base The latter
`or proton donor yields
`is the product produced after the proton is lost
`from
`the acid Notice the diversity in structure of these
`proton donors They include the classic hydrochloric
`acid the weakly acidic dihydrogen phosphate anion
`the ammonium cation such
`as is found in ammo-
`ilium chloride the carboxylic acetic acid the enolic
`form of phenobarbital
`the carboxylic acid moiety of
`indomethacin the imide structure of saccharin and
`the protonated amine of ephedrine Because
`all are
`proton donors they must be treated as acids when
`pHs of
`solution or percentage ioniza
`calculating
`tion of the drug At the same time it will be noted
`shortly that
`there are important differences in the
`pharmaceutic properties of ephedrine hydrochloride
`an acid
`salt of an amine as compared with in
`domethacin phenobarbital or saccharin
`
`

`
`TABLE 2-1
`
`EXAMPLES OF ACIDS
`
`Acid
`
`Hydrochloric acid
`HCI
`
`Sodium dihydrogen phosphate monobasic
`NaH2PO4 Nat H2P04
`Ammonium chloride
`NH4CI NH4 Cl
`
`Acetic acid
`CH3COOH
`
`Phenobarbital
`
`HC
`
`OH
`
`Indomethacin
`
`H2C\
`
`H3CCH
`
`Saccharin
`
`-.
`
`//
`
`NH
`
`00
`
`Ephedrine hydrochloride
`
`CH3
`
`H2N Cl
`
`ACID-BASE PROPERTIES
`
`11
`
`Conjugate Base
`
`HF
`
`sodium phosphate
`
`Cl
`
`NaHPO/
`
`Na
`
`HP042
`
`NH3 Cl
`
`CH3COO
`
`CH3
`
`//
`
`HC\
`HJCCH
`
`Cl
`
`/C
`
`Cl
`
`//
`
`//\\
`
`00
`
`HCl
`
`CH3
`
`HN
`
`OHCH2
`
`The sodium cation and chloride
`
`anion do not
`
`take part
`
`in these reactions
`
`BASECONJUGATE
`
`ACID
`
`The Bronsted-Lowr