WILSON AND G/SVOLD’S
`
`Textbook of Organic Medicinal
`and Pharmaceutical Chemistry
`
`N/nth Edit/on
`
`
`
`EDITED BY
`
`Jaime N. Delgado, Ph.D.
`Division of Medicinal Chemistry, College of Pharmacy
`University of Texas at Austin, Austin, Texas
`
`AND
`
`William A. Fiemers, Ph. D.
`
`Department of Pharmaceutical Sciences, College of Pharmacy
`University of Arizona, Tucson, Arizona
`
`17 Contributors
`
` J. B. Lippincott Company
`
`New York
`
`London Hagerstown
`
`Philadelphia
`
`EXI-||B|T
`ACTAVIS, AMNEAL,
`AUROBWDO,
`BRECKENRIDGE,
`VENNOOT,
`SANDOZ, SUN
`
`|PR2014-01126-1028 p. 1
`
`IPR2014-01126-Exhibit 1028 p. 1
`
`

`
`Production Manager: Janet Greenwood
`Acquisitions Editor: Lisa McAllister
`Manuscript Editor. Marguerite Hague
`Production: Till 8. Till, lnc.
`Compositor: Science Typographers, inc
`Printer/Binder: The Murray Printing Company
`
`Ninth Edition
`
`Copyright © 1991, by J. B. Lippincott Company
`Copyright © 1982 by J. B Lippincott Company
`Copyright © 1977, 1971, 1966, 1962, 1956 by J. B. Lippincott Company
`Copyright © 1954 by J. B. Lippincott Company
`All rights reserved. No part of this book may be used or reproduced in any manner whatsoever without written
`permission except
`for brief quotations embodied in critical articles and reviews Printed in the United States of
`America. For information write J. B. Lippincott Company, East Washington Square, Philadelphia, Pennsylvania 19105.
`654321
`
`Library of Congress Cataloging in Publication Data
`Wilson and Gisvold‘s textbook of organic medicinal and pharmaceutical
`chemistry. ~~ 9th ed. / edited by Jaime N. Delgado and William A.
`Flemers : 17 contributors.
`p.
`cm.
`Includes bibliographical references.
`includes index.
`lSBN 0-397-50877~8
`2. Chemistry, Organic.
`1. Chemistry, Pharmaceutical.
`Charles Owens, 1911 —
`.
`ll. Gisvold, Ole, 1904-
`Jaime N.
`lV. Remers, William A. (William Alan), 1932—
`V. Title: Textbook of organic medicinal and pharmaceutical
`chemistry.
`1. Chemistry, Pharmaceutical. QV 744 W754]
`[DNLM.
`1991
`RS403.T43
`615'.19~dc2O
`DNLM / DLC
`for Library of Congress
`
`I. Wilson,
`.
`Ill. Delgado,
`
`90-13652
`ClF’
`
`The authors and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are
`in accord with current recommendations and practice at the time of publication. However, in view of ongoing research,
`changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions,
`the reader is urged to check the package insert for each drug for any change in indications and dosage and for
`added warnings and precautions. This is particularly important when the recommended agent is a new or infrequently
`employed drug.
`
`|PR2014—01126—EXhibit 1028 p. 2
`
`IPR2014-01126-Exhibit 1028 p. 2
`
`

`
`
`
`CHAPTER’ 2
`
`Physicochemical Properties
`in Relation to Biologic Action
`
`John H. B/ock
`
`INTRODUCTION
`
`Modern drug design, as compared with, Let’s make
`a change on an existing compound or synthesize a
`new structure and see what happens,
`is a fairly
`recent discipline still in its infancy. It is based on
`modern chemical techniques utilizing recent knowl-
`edge of disease mechanisms and receptor properties.
`A 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-
`tient is required, along with the structural charac-
`teristics of the receptor. Acid—base 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 techniques, such
`as regression analysis. Conformational analysis per-
`mits the medicinal chemist
`to predict the drug’s
`three-dimensional shape that is seen by the recep-
`tor. With the isolation and structural determination
`
`of specific receptors and the availability of computer
`software that can estimate the three-dimensional
`
`is possible to design
`it
`shape of the receptor,
`molecules that will show an optimum fit
`to the
`receptor.
`
`HISTORY
`
`Initially, drugs were extracted from plant sources to
`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.
`
`Early drug design started with elucidation of the
`structure of the natural product, followed by selec-
`tive changes in the molecule. The latter was done
`for many reasons,
`including the reduction of an
`undesirable pharmacologic response (side effect); ob-
`taining a better pharmacokinetic response; altering
`the drug’s metabolism; securing a more plentiful,
`less costly supply; and producing a 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 liability. This
`tremendous effort in numerous research laborato-
`
`ries, over many years and involving many scientists,
`had been minimally successful until a better un-
`derstanding of the opiate receptor developed (see
`Chap. 9).
`In other examples, there has been good success at
`this empirical approach. Alteration of the cocaine
`structure has led to the very successful local anes-
`thetics that lack cocaine’s 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 a discipline be-
`came more intense in the 19005, but many of the
`so—called principal compounds still were based on a
`natural product, a fortuitous observation, or an un-
`suspected chemical reaction. The phenothiazines (see
`Chap. 9) were first synthesized as antihistamines,
`but a careful pharmacologic evaluation led to their
`use as major tranquilizing agents that revolution-
`ized the care of the severely mentally ill patient. The
`benzodiazepines (see Chap. 9) originated from an
`unexpected ring enlargement and resulted in a very
`important group of central nervous system relax-
`ants.
`
`Economic factors have stimulated the type of sci-
`entific investigations required to carry out focused
`
`3
`
`IPRZO14-01126-Exhibit 1028 p. 3
`
`IPR2014-01126-Exhibit 1028 p. 3
`
`

`
`4 |
`
`PHYSICOCHEMICAL PROPERTIES IN RELATION TO BIOLOGICAL ACTION
`
`new drug development. It has become increasingly
`costly to develop a new drug that will be approved
`by the U. S. Food and Drug Administration (FDA).
`At one time, safety was the main criterion for FDA
`approval. Today, demonstration of efficacy is an es-
`sential requirement, along with safety considera-
`tions. This has led to (1) increased basic research on
`
`the disease process for which a drug treatment is
`sought, (2) mathematically modeling the pharma-
`cokinetics of the drug’s distribution, (3) elucidation
`of the biochemistry of the pharmacologic response
`from the drug, (4) learning the metabolic fate of the
`drug, (5) defining those specific structural character-
`istics of the drug responsible for the desired phar-
`macologic response, and (6), where possible, visualiz-
`ing the structural characteristics of the receptor.
`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-
`
`gation that has led to the design of today’s new
`agents, a better understanding of the drug’s mecha-
`nism of action is known. Indeed, this is an exciting
`time to practice pharmacy.
`
`OVERVIEW
`
`A drug is a chemical molecule. Following introduc-
`tion into the body, a drug must pass through many
`barriers, survive alternate sites of attachment and
`storage, and avoid significant metabolic destruction
`before it reaches the site of action, usually a recep-
`tor on or in a cell (Fig. 2-1). At the receptor, the
`following equilibrium usually holds.
`
`Drug + Receptor : Drug—Receptor Complex
`l
`Pharmacologic Response
`(Rx. 2-1)
`
`Oral
`Administration
`
`Gastrointestinal
`Tract
`
`Intramuscular
`or
`Subcutaneous
`
`Injection
`
`Intravenous
`Injection
`
`Receptors
`for
`Desired
`Effects
`
`
`
`DRUG
`
`DRUG
`
`DRUG
`
`DRUG-DRUG METABOLITES
`
`onus ——¢_~__.——-
`
`svsremc cmcuumou
`
`DRUG
`
`DRUG METABOLITES
`
`DRUG-DRUG HETABOLITES
`
`DRUG-DRUG METABOLITES
`
`DRUG-DRUG HETABOLITES
`
`
`
`i‘Liver:
`
`
`bile
`site of most drug metabolism l —-~—>
`Intestinal
`Receptors
`duct
`Tract
`for
`Undesired
`
`Feces
`
`Excretion of DRUG—DRUG
`METABOLITES
`
`Effects
`
`
`
`—— Drug administered directly into systemic circulation.
`
`FIG. 2-1. Summa/y of drug d/smbunon: So/id bars: Drug must pass lhrough membranes. Broken /mes: Drug adm/nis[ered directly /nlo
`systemic circulation.
`
`|PR201401126EXhmH1028p.4
`
`IPR2014-01126-Exhibit 1028 p. 4
`
`

`
`The ideal drug molecule will show favorable-binding
`characteristics to the receptor, such that the equilib-
`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. 8) and a few inhibitors
`of the enzyme, acetylcholinesterase (see Chap. 12).
`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 alkylating agents,
`the cell would be replaced,
`ideally with a normal cell. In other words, the usual
`use of drugs in medical treatment call for the drug’s
`effect to last for only a finite period. Then, if it is to
`be repeated, the drug will be administered again. If
`the patient does not tolerate the drug well, it is even
`more important that the agent dissociate from the
`receptor and be excreted from the body.
`
`DRUG DISTRIBUTION
`
`ORAL ADMINISTRATION
`
`An examination of the obstacle course (see Fig. 2-1)
`faced by the drug will give a better understanding of
`what is involved in developing a 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
`solution as they enter the acidic stomach and then
`pass into the alkaline intestinal tract. (This will be
`explained further in the discussion on acid—base
`chemistry.) The ability of the drug to dissolve is
`governed by several factors, including its chemical
`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
`of the drug, it is possible to have a drug dissolve
`quickly or slowly, the latter being the situation for
`many of the sustained-action products. An example
`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 a limited
`
`extent. For example, sulfasalazine, used in the treat-
`ment of ulcerative colitis, passes through a substan-
`tial portion of the intestinal tract before being me-
`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 I
`
`5
`
`O
`
`N
`Cl?
`HOCHJ
`HOICINNQ/H<n>
`
`__
`
`‘T
`
`\
`
`Sulfasalazine
`
`O
`
`Any compound passing through the gastrointesti-
`nal tract will encounter the many and various diges-
`tive enzymes that, in theory, can degrade the drug
`molecule. In practice, when a new drug entity is
`under investigation, it will probably be dropped from
`further consideration if it is found unable to survive
`
`in the intestinal tract. An exception would be a drug
`for which there is no other effective product avail-
`able, or one that provides a more effective treatment
`over existing products and can be administered by
`an alternate route, usually parenteral.
`In contrast, these same digestive enzymes can be
`used to advantage. Chloramphenicol 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
`acid moiety is added as an ester of the chloram-
`phenicol’s primary alcohol. This reduces the parent
`drug’s water solubility so much that it can be for-
`mulated as a 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, chloramphenicol,
`and the very common dietary fatty acid, palmitic
`acid.
`
`NHCOCHC5
`I
`
`o2N—«<::>»-cHcHcH2oR
`
`OH
`
`Chloramphenicol: R = H;
`
`‘P
`Chloramphenicol Palmitale: R = C(CH2),4CH3
`
`Sulfasalazine and chloramphenicol palmitate are
`examples of prodrugs. Most prodrugs are com-
`pounds that are inactive in their native form, but
`are easily metabolized to the active agent. Sulfasala-
`zine and chloramphenicol palmitate are examples of
`prodrugs that are cleaved to smaller compounds, one
`of which will be the active drug. Others are metabolic
`precursors to the active form. An example of this
`type of prodrug is menadione, a simple naph-
`thoquinone, which is converted in the liver
`to
`vitamin K290).
`
`IPRZO14-01126-Exhibit 1028 p. 5
`
`
`IPR2014-01126-Exhibit 1028 p. 5
`
`

`
`6
`
`I
`
`PHYSICOCHEMICAL PROPERTIES IN RELATION TO BIOLOGICAL ACTION
`
`0 0
`
`CH3
`
`CH3
`
`CH3
`Vitamin K 2,20)
`
`CH3
`
`Occasionally the prodrug approach is used to en-
`hance the absorption of a 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.
`
`OOH
`O\\/
`H
`i
`NT N
`C\ ::
`CH3
`
`O
`EnaIapriIiC Acid: R -— H
`
`R\
`
`,C\\
`
`O
`‘ Enalapril: R = CZHS;
`
`Unless the drug is intended to act locally in the
`gastrointestinal tract, it will have to pass through
`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 tract, the lipid
`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-
`trointestinal tract, and the aqueous environment of
`venous circulation. Some very lipid—soluble drugs
`may follow the route of dietary lipids by becoming
`part of the mixed micelles, passing through the
`mucosa cells into the thoracic duct of the lymphatic
`system and then into the venous circulation.
`The drug’s 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
`a highly ordered structure. Part of this membrane is
`a series of channels or tunnels that form, disappear,
`and reform. There are receptors that move com-
`pounds into the cell by a process called pinocytosis.
`
`Most drug molecules are too large to enter the cell
`by an active transport mechanism through the pas-
`sages. On the other hand, some drugs do resemble a
`normal metabolic precursor or intermediate, and
`they can be actively transported into the cell.
`
`PAFIENTEFIAL ADMINISTRATION
`
`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
`precluded. But that does not mean that the drug
`administered by injection is not confronted by obsta-
`cles (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-
`cific organs or areas of the body. Intraspinal and
`intracerebral routes will place the drug directly into
`the spinal fluid or brain, respectively, bypassing a
`specialized tissue,
`the blood-brain barrier, which
`protects the brain from exposure to diverse metabo-
`lites and chemicals. The blood—brain barrier is com-
`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 a drug directly on
`the desired nerve. A spinal block is a form of anes-
`thesia performed by injecting a local anesthetic di-
`rectly into the spinal cord at a specific location to
`block transmission along specific neurons.
`
`IPR2014—01126-Exhibit1028 p. 6
`
`IPR2014-01126-Exhibit 1028 p. 6
`
`

`
`Many of the injections a patient will experience in
`a lifetime will be subcutaneous or intramuscular.
`
`These parenteral routes produce a depot in the tis-
`sues (see Fig. 2.1) from which the drug must reach
`the blood or lymph to produce systematic effects.
`Once in systemic circulation, the drug will undergo
`the same distributive phenomena as orally and in-
`travenously administered agents.
`In general,
`the
`same factors that control the drug’s 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
`increase the flexibility in possible dosage forms. The
`solubility of methylprednisolone can be altered from
`essentially water-insoluble methylprednisolone ac-
`etate,
`to slightly water—insoluble methylpred-
`nisolone,
`to water-soluble methylprednisolone
`sodium succinate. The water-soluble sodium succi-
`
`nate salt is used in oral, intravenous, and intramus-
`cular dosage forms. Methylprednisolone,
`itself,
`is
`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-
`prednisolone by the patient’s own systemic hydro-
`lytic enzymes.
`
`
`
`(EH,
`Methylprednisolone (R = H)
`Ester Available:
`
`Methylprednisolone Acetate: R = COCH3
`Salt Available:
`Methylprednisolone Sodium Succinate:
`
`R = COCH2CH2COO‘Na*
`
`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, a new equi-
`librium must be considered. Depending on the equi-
`librium constant, the drug can remain in systemic
`circulation bound to albumin for a considerable pe-
`riod and be unavailable to the sites of biotransfor-
`
`mation, the pharmacologic receptors, and excretion.
`
`onus DISTRIBUTION I
`
`7
`
`Drug + Albumin : Drug—Albumin Complex
`
`(Rx. 2-2)
`
`The effect of protein binding can have a profound
`result on the drug’s effective solubility, biodistribu-
`tion, half-life in the body, and interaction with other
`drugs. A drug with such poor water solubility that
`therapeutic concentrations of the unbound (active)
`drug normally cannot be maintained, still can be a
`very effective agent. The albumin—drug complex acts
`as a reservoir by providing concentrations of free
`drug large enough to cause a pharmacologic re-
`sponse.
`
`Protein binding may also limit access to certain
`body compartments. The placenta is able to block
`passage of proteins from maternal to fetal circula-
`tion. Consequently, drugs that normally would be
`expected to cross the placenta barrier and possibly
`harm the fetus are retained in the maternal circula-
`
`tion bound to the mother’s serum proteins.
`Protein binding also can prolong the drug’s dura-
`tion of action. The drug—protein complex is too large
`to pass through the renal glomerular membranes,
`preventing rapid excretion of the drug. Protein bind-
`ing limits the amount of drug available for‘biotrans—
`formation (see later and Chap. 3) and for interaction
`with specific receptor sites. For example the try-
`panocide, suramin,
`remains in the body in the
`protein-bound form as long as three months. The
`maintenance dose for this drug is based on weekly
`administration. At first this might seem to be an
`advantage to the patient. It can be, but it also means
`that should the patient have serious adverse reac-
`tions,
`it will require a substantial length of time
`before the concentration of drug falls below toxic
`levels.
`
`The drug~protein-binding phenomenon can lead
`to some interesting drug—drug 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
`
`leading to an increased
`warfarin at the receptor,
`prothrombin time (increased time for clot forma-
`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
`constitutes a depot of considerable importance. The
`more lipophilic the drug is, the more likely it will
`concentrate in these pharmacologically inert depots.
`The short-acting, lipophilic barbiturate, thiopental,
`reportedly disappears
`into tissue protein,
`redis-
`
`|PR2014-01 126-Exhibit 1028 p. 7
`
`
`IPR2014-01126-Exhibit 1028 p. 7
`
`

`
`3
`
`I
`
`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
`initially administered thiopental is present in high
`enough concentrations to combine with its recep-
`tors. In general, structural changes in the barbitu-
`rate series (see Chap. 9) that favor partitioning into
`the lipid tissue stores decreases the duration of
`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.
`
`DRUG METABOLISM
`
`including drugs, metabolites, and
`All substances,
`nutrients that are in the circulatory system, will
`pass through the liver. Most molecules absorbed
`from the gastrointestinal tract will enter the portal
`vein and be transported to the liver. A large propor-
`tion of a drug will partition or be transported into
`the hepatocyte, where it may be metabolized by
`
`hepatic enzymes to inactive chemicals during the
`initial trip through the liver by what is known as the
`first—pass effect. Over 60% of the local anesthetic-
`antiarrhythmic agent, lidocaine, is metabolized dur-
`ing its initial passage through the liver, resulting in
`it being impractical to administer orally. When used
`for cardiac arrhythmias,
`it
`is administered intra-
`venously. This rapid metabolism of lidocajne is used
`to advantage when stabilizing a patient with cardiac
`arrhythmias. Should too much lidocaine be adminis-
`
`0
`
`CH3
`
`/
`NH
`
`/C2H5
`(j\/NH"
`Cl“
`\C2H5
`
`CH3
`
`Lidocaine
`
`0
`CH3
`u
`/CYNH
`
`NH3+ CI‘
`
`CH3
`
`CH3
`
`Tocainide
`
`R
`
`S /
`
`/
`
`N
`
`”AI >
`K-N
`
`NH
`
`Sutindac: R = CH3SO"; Active Sulfide Metabolite: R = CH3S“
`
`o2N
`
`Azathioprene R =
`
`N
`
`;
`
`6—Mercaptopurine: R = H
`
`‘F
`CH3
`
`
`
`CH3
`/
`CH2—CH2—CH2—N\ ~HCt
`R
`
`lmipramine R = CH3
`Desipramine: R = H
`
`Hc—cH42—cH2—N\
`
`-HCt
`
`R
`
`Amitriptyltne: R = CH3
`Nortriptytine: R = H
`
`Phenacetin: R, = C2H5O', R2 = CH3CO‘. R3 = H;
`Acetaminophen: R1 = HO‘ ,R2 = CH3CO', R3: H;
`
`|PR2014—01126—EXhibit 1028 p. 8
`
`IPR2014-01126-Exhibit 1028 p. 8
`
`

`
`tend to
`toxic responses will
`tered intravenously,
`abate because of the rapid biotransformation to in-
`active metabolites. An understanding of
`the
`metabolic labile site on lidocaine led to the develop-
`ment of the primary amine analogue, tocainide. In
`contrast with lidocaine’s half—life of less than two
`hours,
`tocainide’s half-life is about 15 hours with
`40% of the drug excreted unchanged. The develop-
`ment of orally active antiarrhythmic agents is dis-
`cussed in more detail in Chapter 14.
`A study of the metabolic fate of a drug is a
`requirement for all new products. Many times it is
`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 investigations of potentially
`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
`U. S. market) is converted to acetaminophen. In the
`tricyclic antidepressant
`series
`(see Chap.
`10)
`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 3.
`Although a drug’s metabolism can be a source of
`frustration for the medicinal chemist, pharmacist,
`and physician, and can lead to inconvenience and
`compliance problems for the patient, it is fortunate
`that the body has the ability to metabolize foreign
`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-
`lar insecticide, DDT. After entering the body, these
`chemicals sit in body tissues, slowly diffusing out of
`the depots and potentially harming the individual on
`a prolonged basis for several years.
`
`EXCRETION
`
`The main route of excretion of a drug and its
`metabolites is through the kidney. For some drugs,
`
`DRUG DISTRIBUTION l
`
`9
`
`enterohepatic circulation (see Fig. 2-1), in which the
`drug reenters the intestinal
`tract from the liver
`
`through the bile duct, can be an important part of
`the agent’s 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. A 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 for those drugs that
`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
`drug for the receptor is crucial. Reexamine Reaction
`2-1 and Figure 2-1. If the equilibrium does not favor
`formation of the drug—receptor 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 at the
`receptor.
`
`RECEPTOR
`
`With the exception of general anesthetics (see Chap.
`9), the working model for a pharmacologic response
`consists of a drug binding to a specific receptor.
`Many drug receptors actually are used by endoge-
`nously produced ligands. Cholinergic agents interact
`with the same receptors as the neurotransmitter
`acetylcholine. Synthetic corticosteroids bind to the
`same receptors as cortisone and hydrocortisone.
`Many times, receptors for the same ligand will be
`found in a variety of tissues throughout the body.
`The nonsteroidal anti-inflammatory agents
`(see
`Chap. 17) inhibit the prostaglandin-forming enzyme
`cyclooxygenase which is found in nearly every tis-
`sue. This class of drugs has a 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 there are a variety of receptors with
`similar structural requirements found in several
`organs and tissues. Thus,
`the nonsteroidal anti-
`
`|PR2014—01126—EXhibit 1028 p. 9
`
`IPR2014-01126-Exhibit 1028 p. 9
`
`

`
`10l
`
`PHYSICOCHEMICAL PROPERTIES IN RELATION TO BIOLOGICAL ACTION
`
`inflammatory drugs combine with the desired cy-
`cloxygenase receptors at the site of the inflammation
`and the receptors in the gastrointestinal mucosa
`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 blood~brain 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
`of antihistamines. In contrast, some antihistamines
`are used for their central nervous system depressant
`activity, which would imply that a considerable
`amount of the administered dose is crossing the
`blood—brain barrier relative to binding to the his-
`tamine—1 (H1) receptors in the periphery.
`Although it is normal to think of side effects 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-
`fonamides had a hypoglycemic effect (see Chap. 5).
`Nevertheless, a real problem in drug therapy is
`patient compliance to take the drug a 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
`ways to do this, including (1) altering the molecule
`which, in turn, can change the biodistribution, (2)
`increasing the specificity for the desired receptor
`(desired pharmacologic response) while decreasing
`the affinity for undesired receptor (producer of side
`effects), and (3) the still experimental approach of
`attaching the drug to a monoclonal antibody that
`will bind to a specific tissue that is antigenic for the
`antibody. Alteration of biodistribution can be done
`by changing the drug’s solubility, enhancing its abil-
`ity to resist being metabolized (usually in the liver),
`altering the formulation or physical characteristics
`of the drug, and changing the route of administra-
`tion. If a drug molecule can be designed in such a
`way that its binding to the desired receptor is en-
`hanced,
`relative to the undesired receptor, and
`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
`several challenges in designing a bioactive molecule.
`A good fit to a specific receptor is desirable, but the
`
`drug would normally be expected to eventually dis-
`sociate from the receptor. The specificity for the
`receptor would be such that side effects would be
`minimal. The drug would be expected to clear the
`body within a reasonable time. Its rate of metabolic
`degradation should allow reasonable dosing sched-
`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 a compromise product
`that meets a medical need, while demonstrating
`good patient acceptance.
`
`AC|D—BASE 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. A drug’s
`acid—base 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-
`m