F
`
`Fo~e·s Principles of
`Medicinal Chemistr~
`
`FIFTH EDITION
`
`
`Page 1 of 34
`
`SENJU EXHIBIT 2156
`LUPIN v SENJU
`IPR2015-01105
`
`

`
`Foye's Principles of
`Medicinal Chemistry
`
`Fifth Edition
`
`David A. Williams, Ph.D.
`Professor of Chemistry
`Massachusetts College of Pharmacy and Health Sciences
`Boston, Massachusetts
`
`Thomas L. Lemke, Ph.D.
`Associate Dean for Professional Programs and
`Professor of Medicinal Chemistry
`College of Pharmacy
`University of Houston
`Houston, Texas
`
`4~ LIPPI N COTT WILLIAMS & WILKINS
`
`•
`
`A Wolters Kluwer Company
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`Page 2 of 34
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`
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`Copyright© 2002 Lippincott Williams & Wilkins
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`The publisher is not responsible (as a matter of product liability, negligence, or other(cid:173)
`wise) for any injury resulting from any material contained herein. This publication
`contains information relating to general principles of medical care that should not be
`construed as specific instructions for individual patients. Manufacturers' product in(cid:173)
`formation and package inserts should be reviewed for current information, including
`contraindications, dosages, and precautions.
`
`Printed in the United States of America
`
`First Edition, 1974
`
`library of Congress Cataloging-in-Publication Data
`Williams, David A., 1938-
`Foye's principles of medicinal chemistry/DavidA. Williams, Thomas L. Lemke.-5th ed.
`p. em.
`Includes index.
`ISBN 0-683-30737-1
`1. Pharmaceutical chemistry. I. Title: Principles of medicinal chemistry. II. Lemke,
`Thomas L. III. Title.
`
`RS403 .P75 2002
`616.07'56-dc21
`
`2001050327
`
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`03 04 05
`3 4 5 6 7 8 9 10
`
`, . ..
`
`·' ,,
`
`Page 3 of 34
`
`

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`Medicinal chemistry is the discipline concerned with de(cid:173)
`termining the influence of chemical structure on biological
`activity. As such, it is therefore necessary for the medicinal
`chemist to understand not only the mechanism by which a
`drug exerts its effect, but also the physicochemical proper(cid:173)
`ties of the molecule. The term "physicochemical properties"
`refers to the influence of the organic functional groups pres(cid:173)
`ent within a molecule on its acid/base properties, water sol(cid:173)
`ubility, partition coefficient, crystal structure, stereochem(cid:173)
`istry etc. All of these properties influen ce the absorption,
`distribution, metabolism and excretion (ADME) of the mol(cid:173)
`ecule. In order to design better medicinal agents the medic(cid:173)
`inal chemist needs to understand the relative contributions
`, that each functional group makes to the overall physical
`ch emical properties of the molecule. Studies of this type in-
`volve modification of the molecule in a systematic fashion
`and determination of how these changes affect biological ac(cid:173)
`tivity. Such studies are referred to as studies of structure(cid:173)
`activity relationships i.e., what structural features of the mol(cid:173)
`ecule contribute to, or take away from, the desired biologi(cid:173)
`cal activity of the molecule of interest.
`Because of the fundamental nature of its subject matter,
`this chapter includes n umerous case studies throughout
`(as boxes) and at the end. In addition, a list of study ques(cid:173)
`tions at the en d of-and unique to--this chapter provides
`further self-study material on the subject of drug design.
`
`INTRODUCTION
`tun-
`Chemical compounds, usually derived from plants,
`;po-
`have been used by humans for thousands of years to alle(cid:173)
`:}2.
`:28. viate pain, diarrhea, infection and various other maladies.
`)fid Until the 19th century these "remedies" were primarily
`j crude preparations of plant material whose constituents
`were unknown and the nature of the active principal (if
`1 any) was also unknown. The revolution in synthetic or(cid:173)
`ganic chemistry during the 19th century produced a con-
`I certed effort toward identification of the structures of the
`active constituents of these n aturally derived medicinals
`an d synthesis of what were hoped to be more efficacious
`agents. By determining the molecular structures of th e ac-
`tive components of th ese complex mixtures it was thought
`that a better understanding of, how these components
`1
`Worked could be elucidated.
`
`Relationship Between Molecular Structure
`· ilnd Biologic Activity
`Early studies of the relationship between chemical
`, Stru cture an d biologic activity were conducted by Crum-
`
`2. Drug Design and Relationship of Functional Groups
`to Pharmacologic Activity
`
`JAMES KNITTEL AND ROBIN ZAVOD
`
`..
`
`. , ~ · >·· •
`
`Brown and Fraser (1) in 1869. They showed that many
`compounds containing tertiary amine groups became
`muscle relaxants when converted to quaternary ammo(cid:173)
`nium compounds. Compounds with widely differing ph ar(cid:173)
`macological properties such as, strychnine (a convulsant),
`morphine (an analgesic) , nicotine (deterrent, insecti(cid:173)
`cide), and atropine (anticholinergic), all could be con-
`- verted to muscle relaxants with properties similar to
`tubocurarine when methylated (Fig. 2.1). Crum-Brown
`and Fraser therefore concluded that muscle relaxant ac(cid:173)
`tivity required a quaternary ammonium group within the
`chemical structure. This initial hypothesis was later dis(cid:173)
`proven by the discovery of the natural neurotransmitter
`and activator of muscle contraction , acetylcholine (Fig.
`2.2) . Even though Crum-Brown and Fraser's initial hy(cid:173)
`pothesis concerning chemical structure and muscle relax(cid:173)
`ation was proven to be incorrect, it demonstrated the con(cid:173)
`cept
`that molecular structure does
`influence
`the
`biological activity of chemical compounds.
`With the discovery by Crum-Brown and Fraser that qua(cid:173)
`ternary ammonium groups could produce compounds
`with muscle relaxant properties scientists began looking
`
`yH3
`
`,..../t\!Hs G
`Q_)._{ X
`
`HO
`
`O'
`
`,OH
`
`Morphine
`(analgesic)
`
`N-Methylmorphine
`(muscle relaxant)
`
`,..
`Q e
`
`X
`
`0
`
`"
`li H3C CH3
`
`Nicotine
`(insecticide)
`
`N-Methylnicotine
`(muscle relaxant)
`
`Atropine
`(mydriatic)
`
`N-Methylatropine
`(muscle relaxant)
`
`Fig. 2.1. Effects of methylation on biologic activity.
`
`37
`
`Page 4 of 34
`
`

`
`38
`
`Fig. 2.2. Acetylcholine, a neurotransmitter and muscle relaxant.
`
`for other organic functional groups that would produce
`specific biologic responses. The thinking at this period of
`time was that specific chemical groups, or nuclei (rings),
`were responsible for specific biologic effects. This lead to
`the postulate, which took some time to disprove, that "one ·
`chemical group gives one biological action." (2) Even af(cid:173)
`ter the discovery of acetylcholine by Loewi and Navrati (3)
`which effectively dispensed with Crum-Brown and Fraser's
`concept of all quaternary ammonium compounds being
`muscle relaxants, this was still considered dogma and took
`a long time to replace.
`
`Selectivity of Drug Action
`and Drug Receptors
`Though the structures of many drugs or xenobiotics
`were known at the turn of the century, or at least the com(cid:173)
`position of functional groups, it was still a mystery as to
`how these compounds exerted their effects. Utilizing his
`observations regarding the staining behavior of microor(cid:173)
`ganisms, Ehrlich developed the concept of drug receptors
`( 4). He postulated that certain "side chains" on the sur(cid:173)
`faces of cells were "complementary" to the dyes (or drug),
`thereby allowing the two substances to combine. In the
`case of antimicrobial compounds, this combining of the
`chemical to the "side chains" produced a toxic effect. This
`concept effectively was the first description of what later
`became know as the receptor hypothesis for explaining
`the biological action of chemical compounds. Ehrlich also
`discussed selectivity of drug action via the concept of a
`"magic bullet" for compounds that would eradicate dis(cid:173)
`ease states without producing undue harm to the organ(cid:173)
`ism being treated (i.e., the patient). This concept was later
`modified by Albert (5) and is generally referred to as "se(cid:173)
`lective toxicity. " Utilizing this concept Ehrlich developed
`organic arsenicals that were toxic to trypanosomes as a re(cid:173)
`sult of their irreversible reaction with mercapto groups
`present on vital proteins within the organism. The forma(cid:173)
`tion of As-S bonds resulted in death to the target organ(cid:173)
`ism. However, it was soon learned that these compounds
`were not only toxic to the target organism, but also to the
`host once certain blood levels of arsenic were achieved.
`The "paradox" that resulted after the discovery of
`acetylcholine of how one chemical group can produce two
`different biologic effects, i.e., muscle relaxation and mus(cid:173)
`cle contraction, was explained by Ing (6) using the actions
`of acetylcholine and tubocurarine as his examples. Ing hy(cid:173)
`pothesized that both acetylcholine and tubocurarine act at
`the same receptor but that one molecule fits to the recep(cid:173)
`tor in a more complementary manner and "activates" it,
`causing muscle contraction. Just how this activation occurs
`
`PART I I PRINCIPLES OF DRUG DISCOVERY
`
`was not elaborated upon. The larger molecule, tubocu(cid:173)
`rarine, simple occupies part of the receptor and prevents
`acetylcholine, the smaller molecule, from occupying the
`receptor. With both molecules the quaternary ammonium
`functional group is a common structural feature and in(cid:173)
`teracts with the same region of the receptor. If one closely
`examines the structures of other compounds that have
`opposing effects on the same pharmacologic system, this
`appears to be a common theme: Molecules that block the
`effects of natural neurotransmitters (antagonists) are gen(cid:173)
`erally larger in size than the native compound. Both com(cid:173)
`pounds share common structural features, however, thus
`providing support to the concept that the structure of a
`molecule, its composition and arrangement of chemical
`functional groups, determines the type of pharmacologic
`effect that it possesses (i.e., structure-activity relationship).
`Thus, compounds that are muscle relaxants acting via the
`cholinergic nervous system will possess a quaternary am(cid:173)
`monium or protonated tertiary ammonium group and will
`be larger than acetylcholine. Structure-activity relation(cid:173)
`ships (SARs) are the underlying principle of medicinal
`chemistry. Similar molecules exert similar biological ac(cid:173)
`tions in a qualitative sense. A corollary to this is that struc(cid:173)
`tural elements (functional groups) within a molecule most
`often contribute in an additive manner to the physico(cid:173)
`chemical properties of a molecule and therefore its bio(cid:173)
`logical action. One need only peruse the structures of
`drug molecules in a particular pharmacologic class to be(cid:173)
`come convinced of this (e.g., histamine H 1 antagonists;
`histamine H 2 antagonists; [3-adrenergic antagonists; etc.).
`The objective of the medicinal chemist in his/her quest
`for better medicinal agents (drugs) is to discover what
`functional groups within a specific structure are important
`for its pharmacologic activity, and how can these groups
`be modified to produce more potent, selective and safer
`compounds.
`An example of how different functional groups can yield
`compounds with similar physicochemical properties is
`shown with sulfanilamide antibiotics. In Figure 2.3 the
`structures of sulfanilamide and p-aminobenzoic acid
`(PABA) are shown. In 1940, Woods (7) demonstrated that
`PABA was capable of reversing the antibacterial action of
`sulfanilamide (and other sulfonamides antibacterials) and
`that both PABA and sulfanilamide had similar steric and
`electronic properties. Both compounds contain acidic func-
`
`¢
`
`O=S=O
`H,N 0
`
`l9A
`
`p-Aminobenzoic acid
`
`Sulfanilamide
`
`Fig. 2.3.
`Ionized forms of PABA and sulfanilamide. Comparison of
`distance between amine and ionized acids of each compound. Note
`how closely sulfanilamide resembles PABA.
`
`Page 5 of 34
`
`

`
`cHAPTER 2 I DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY
`
`39
`
`·onal groups with PABA containing ;m aromatic carboxylic
`~cid and sulfanilamide an aromatic sulfonamide. When ion(cid:173)
`. ed at physiological pH both compounds have a similar
`~ectronic configuration and the distance between the ion(cid:173)
`ized acid and the weakly basic amino group is also very sim(cid:173)
`ilar. It should therefore be no surprise that sulfanilamide
`acts as an antagonist to PABA metabolism in bacteria.
`
`pHYSICOCHEMICAL PROPERTIES OF DRUGS
`Acid/Base Properties
`The human body is composed of 70-75% water, which
`amounts to approximately 55 liters of water for a 160 lb (55
`kg) individual. For an average drug molecule with a molec(cid:173)
`ular weight of 200 g/mol and a dose of 20 mg this leads to
`a concentration of -2 X 10-6 M solution. When consider(cid:173)
`ing the solution behavior of a drug within the body we are
`therefore dealing with a dilute solution. For dilute solutions
`the Bronsted-Lowry (8) acid/base theory is most appropri(cid:173)
`ate for explaining and predicting acid/base behavior. This
`is a very important concept in medicinal chemistry since the
`acid/base properties of drug molecules direcdy affect ab(cid:173)
`sorption, excretion and compatibility with other drugs in
`solution. According to the Bronsted-Lowry Theory an acid
`is any substance capable of yielding a proton (H+) and a
`base is any substance capable of accepting a proton. When
`an acid gives up a proton to a base it is converted to its con(cid:173)
`jugate base. Similarly, when a base accepts a proton it is con(cid:173)
`verted to its conjugate acid form (Equations 2.1 and 2.2).
`CH3COOH + H 20 == CH,C008 + H 3d:B
`
`Eq. 2.1
`
`Eq. 2.2
`
`Acid
`(acetic acid)
`
`Base
`(water)
`
`Conjugate Conjugate
`base
`acid
`(acetate)
`(hydronium)
`
`CH,NH2 + H 20 == CH3NH3 ® + 8 oH
`
`Conjugate
`Conjugate
`Acid
`Base
`base
`Acid
`(methylamine) (water)
`(methylammonium) (hydroxide)
`
`Note that when an acid loses its proton it is left with an
`extra pair of electrons that are no longer neutralized by the
`proton. This is the ionized form of the acid and is now very
`water soluble due to the charge. Since the acid has lost its
`proton it is often also referred to as having undergone dis(cid:173)
`sociation. There are many different organic functional
`groups that behave as acids and these are listed in Table 2.1.
`It is important that the student learn to recognize these
`functional groups and their relative acid strengths. This will
`help the student to predict absorption, distribution, excre(cid:173)
`tion and potential incompatibilities between drugs.
`When a base is converted to its conjugate acid form it
`too becomes ionized. However, in this instance it becomes
`positively charged due to the presence of the extra proton.
`Most basic drugs are usually derived from primary, sec(cid:173)
`ondary and tertiary amines. Other organic functional
`groups that act as bases are shown in Table 2.2. Again the
`
`student should familiarize himself with these functional
`groups and be able to readily recognize them by name and
`relative strengths.
`Organic functional groups that are neither capable of
`giving up a proton, nor accepting a proton are considered
`to be neutral (or nonelectrolytes) with respect to their
`acid/base properties. Common functional groups of this
`type are shown in Table 2.3. In the case of quaternary am(cid:173)
`monium compounds the molecule is not electrically neu(cid:173)
`tral even though it is neither acidic nor basic. Additional
`reading on the acid/base behavior of the functional
`groups listed in Tables 2.1-2.3 can be found in Remington
`(9) and Lemke (10).
`A molecule may contain multiple functional groups and
`therefore possess both acid and base properties. For exam(cid:173)
`ple, ciprofloxacin (Fig. 2.4) a quinolone antibiotic, con(cid:173)
`tains a secondary alkyl amine and a carboxylic acid. De(cid:173)
`pending upon the pH of the solution (or tissue) this
`molecule will either accept a proton, yield a proton or
`both. Thus it can be a base, acid or amphoteric (both acid
`and base) in its properties. Figure 2.5 shows the acid/base
`behavior of ciprofloxacin at two different locations of the
`gastro-intestinal tract. Note that at a given pH value (e.g.,
`pH of 1.0-3.5) only one of the functional groups (the alkyl(cid:173)
`amine) is ionized. In order to be able to make this predic(cid:173)
`tion one has to understand the relative acid/base strength
`of acids and bases. Thus, one needs to be able to know
`which acid or base within a molecule containing multiple
`functional groups is the strongest and which is the weakest.
`The concept of pK, not only indicates the relative
`acid/base strength of organic functional groups, but it also
`allows one to calculate, for a given pH, exacdy how much
`of the molecule is in the ionized and unionized form.
`
`Relative Acid Strength (pKa)
`Strong acids and bases completely dissociate or accept
`a proton in aqueous solution to produce their respective
`conjugate bases and acids. For example, mineral acids
`such as HCl or bases such as NaOH undergo complete dis(cid:173)
`sociation in water with the equilibrium shifted completely
`to the right side as shown in equations 2.3 and 2.4:
`
`Eq. 2.3
`
`HCI + H.O
`
`Eq. 2.4
`
`However, acids and bases of intermediate or weak
`strength incompletely dissociate or accept a proton and
`the equilibrium lies somewhere in between. The equilib(cid:173)
`rium is such that all possible species may exist. Note that
`in equations 2.3 and 2.4 water is acting as a base in one in(cid:173)
`stance and as an acid in the other. Water is amphoteric, it
`may act as an acid or a base depending upon the condi(cid:173)
`tions. Because we are always dealing with a dilute aqueous
`solution the strongest base that can be present is OH- and
`the strongest acid H 30+. This is known as the leveling ef-
`
`Page 6 of 34
`
`

`
`40
`
`PART I I PRINCIPLES OF DRUG DISCOVERY
`
`Table 2.1. Common Acidic Organic Functional Groups andTheir Ionized (Conjugate Base) Forms
`
`Acids
`
`Phenol
`
`pKa
`
`9-11
`
`Sulfonamide
`
`9-10
`
`Imide
`
`9-10
`
`~OH
`
`R-v
`
`0
`II
`R-~-NH2
`0
`
`8
`
`~0 R-v
`
`0 8
`II
`R-S-NH
`II
`0
`
`Alkylthiol
`
`10-11
`
`R-SH
`
`e
`R-S
`
`Conjugate Base
`
`Phenolate
`
`Sulfonamidate
`
`lmidate
`
`Th iolate
`
`Thiophenolate
`
`N-Arylsulfonamidate
`
`0,/? f
`
`R~ 8'N"" R'
`
`Sulfonimidate
`
`crs
`
`8
`
`R -
`
`c;;8
`R-S-N-o
`0
`\.~
`A"
`
`0,/? 1
`R ~S,N R' =
`8
`
`Thiophenol
`
`9-10
`
`R O
`'n
`
`SH
`
`N-Arylsulfonamide
`
`6-7
`
`Sulton imide
`
`5-6
`
`R-S-N
`II H
`0
`
`I .'""'.:
`}\
`. ~
`1-l"
`
`0 11 -o
`0,/? 1
`R~ 8'N
`H
`
`R'
`
`Alkylcarboxylic acid
`
`5-6
`
`0
`II
`R-C-OH
`
`0 8
`II
`R-C-0
`
`Alkylcarboxylate
`
`Arylcarboxylic acid
`
`4-5
`
`Sulfonic acid
`
`0-1
`
`Acid strength usually increases as one moves down the table.
`
`8
`~coo
`
`R-v-
`
`Aryl carboxylate
`
`Sulfonate
`
`Page 7 of 34
`
`

`
`cHAPTER z f DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY
`
`41
`
`Table 2.2. common Basic Organic Functional Groups and Their Ionized (Conjugate Acid) Forms
`Conjugate Acid
`pKa
`aas~e~-----------------------------------------------------------------------------------
`Arylammonium
`~NH2
`~NH3(±)
`R-v
`R-v-
`Arylam ine
`4- 5
`
`Aromatic amine
`
`5- 6
`
`Aromatic ammonium
`
`Imine
`
`3- 4
`
`R-C=NH
`H
`
`(±)
`R-C=NH
`H
`
`lminium
`
`Alkylamines
`
`10-11
`
`9- 10
`
`Amidine
`
`10-11
`
`Guanidine
`
`10-1 1
`
`Alkylammonium
`
`Amidinium
`
`Guanidinium
`
`Table 2.3. Common Organic Functional Groups That Are Considered Neutral Under Physiologic Conditions
`
`R- CH2-0H
`Alkyl alcohol
`
`0
`)l
`R NH2
`
`Amide
`
`R'
`R-N-- o
`I
`R"
`
`Amine oxide
`
`0
`
`R'
`
`' R'
`
`Ether
`
`H
`
`erN~
`
`R
`
`R'
`
`Diarylamine
`
`0
`
`R)l_R'
`
`Ester
`
`Sulfonic acid ester
`
`R-C:N
`
`Nitril e
`
`R'(±)
`I
`R-N-R"
`I
`R"'
`
`Quaternary ammonium
`
`Ketone & Aldehyde
`
`Thioether
`
`Sulfoxide
`
`Sulfone
`
`11-.a~-------------------------------------------------------------~~
`
`Page 8 of 34
`
`

`
`42
`
`ketone, neutral
`
`aryl am ine, weak base
`
`alkyl amine
`basic
`
`Fig. 2.4. Chemical structure of ciprofloxacin show ing the various or(cid:173)
`ganic functional groups.
`
`0 FroC02H
`I.±J ('N
`N
`H-~.J A
`
`H
`
`Stomach (pH 1.0- 3.5)
`
`Duodenum (pH -4)
`
`Fig. 2.5. Predominate forms of ciprofloxacin at two different locations
`w ithin the gastrointestinal tract.
`
`feet of water. Thus, some organic functional groups that
`are considered acids or bases with respect to their chemi(cid:173)
`cal reactivity do not behave as such under physiological
`conditions in aqueous solution. For example, alkyl alco(cid:173)
`hols such as ethyl alcohol, are not sufficiently acidic to un(cid:173)
`dergo ionization to a significant extent in aqueous solu(cid:173)
`tion. Water is not sufficiently basic to remove the proton
`from the alcohol to form the ethoxide ion (Equation 2.5).
`
`Eq. 2.5 CH,CH,OH + H,O ---=~= CH,CH,O + H,o<±>
`
`Absorption/ Acid-Base Case
`
`PART I I PRINCIPLES OF DRUG DISCOVERY
`
`Predicting the Degree of Ionization
`of a Molecule
`From general principles it is possible to predict if a mol(cid:173)
`ecule is going to be ionized or unionized at a given pH
`simply by knowing if the functional groups present on the
`molecule are acid or basic. However, in order to be able to
`quantitatively predict the d egree of ionization of a mole(cid:173)
`cule one must know the pi<, values of the acid and basic
`functional groups present and the pH of the environment
`to which the compound will be exposed. The Henderson(cid:173)
`H assalbach equation (Equation 2.6) can be used to calcu(cid:173)
`late the percent ionization of a compound at a given pH.
`This equation was used to calculate the major forms of
`ciprofloxacin in Figure 2.5.
`
`Eq. 2.6
`
`pK, =
`
`pH +
`
`log
`
`[acid form]
`[base form ]
`
`The key to understanding the use of the Henderson(cid:173)
`Hassalbach equation for calculating percent ionization is to
`realize that this equation relates a constant, pK., to the ratio
`of acid form to base form of the drug. Since pK. is a constant
`for any given molecule, then the ratio of acid to base will de(cid:173)
`termine the pH of the solution. Conversely, a given pH de(cid:173)
`termines the ratio of acid to base. A sample calculation is
`shown in Figure 2.6 for the sedative hypnotic amobarbital.
`When dealing with a base, the student must recognize
`that the conjugate acid form is the ionized form of the
`drug. Thus, as one should expec t, a base behaves in a
`manner opposite to that of an acid. Figure 2. 7 shows the
`calculated percent
`ionization for
`the decongestant
`
`A long distance truck driver comes into the pharmacy complaining of seasonal allergies. He asks you to recommend
`an agent that will act as an antihistamine, but will not cause drowsiness. He regularly takesTUMs for indigestion be(cid:173)
`cause of the bad food that he eats while he is on the road.
`
`a
`
`Cetirizine (Zyrtec)
`
`Clemastine (Tavist)
`
`Olopatadine (Patanol)
`
`1. Identify the functional groups present in Zyrtec andTavist and evaluate the effect of each functional group on the
`ability of the drug to cross lipophilic membranes (e.g., blood brain barrier). Based on your assessment of each
`agent's ability to cross the blood brain barrier (and therefore potentially cause drowsiness), provide a rationale for
`whether the truck driver should be taking Zyrtec, orTavist.
`2. Patanol is sold as an aqueous solution of the hydrochloride salt. Modify the structure above to show the appropriate
`salt form of this agent. This agent is applied to the eye to relieve itching associated with allergies. Describe why this
`agent is soluble in water and what properties make it able to be absorbed into the membranes that surround the eye.
`3. Consider the structural features of Zyrtec andTavist. In which compartment will each of these two drugs be best
`absorbed? (stomach, pH = 1 or intestine, pH = 7.5).
`4. TUMs neutralizes stomach acid (pH of stomach = 3.5). Based on your answer to question #3, determine whether the
`truck driver will get the full antihistaminergic effect if he takes his antihistamine at the same time as he takes his
`TUMs. Provide a rationale for your answer.
`
`Page 9 of 34
`
`

`
`cHAPTER 2 I DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY
`
`43
`
`-----
`
`Acid Base Chemistry/Compatibility Cases
`
`The IV technician in the hospital pharmacy gets an order for a patient that includes the two drugs drawn below. She is un(cid:173)
`sure if she can mix the two drugs together in the same IV bag and isn't sure how water-soluble either of the agents are.
`
`0
`
`H H
`
`r7Yo~N-:.J=rs cH3
`V
`ti 0 • N-{<cH3
`
`C0£1<+
`
`H;JC,N H
`_; H
`
`···oH
`
`-
`
`Penicillin V Potassium
`
`H;
`
`Codeine Phosphate
`
`1. Penicill in V potassium is drawn in its salt form, whereas codeine phosphate is not. Modify the structure above to
`show the salt form of codeine phosphate. Determine the acid/base character of the functional groups in the two
`molecules drawn above, as well as the salt form of codeine phos.phate.
`2. As originally drawn above, which of these two agents is more water-soluble? Provide a rationa le for your selection
`that includes appropriate structural properties. Is the salt form of codeine phosphate more or less water soluble
`than the free base form of the drug? Provide a rationale for your answer based on the structural properties of the
`salt form of codeine phosphate.
`3. What is the chemical consequence of mixing aqueous solutions of each drug in the same IV bag? Provide a ration(cid:173)
`ale that includes an acid/base assessment.
`
`Acid form
`pKa 8.0
`
`Conjugate base
`
`Question: At a pH of 7.4, what is the percent ionization of amobarbital?
`[ acid l
`8.0 = 7.4 + log [base]
`
`Answer:
`
`Base form
`
`Conjugate acid form
`pKa 9.4
`
`Question: What is the percent ionization of phenylpropanolamine
`at pH 7.4?
`Answer: 9.4 = 7.4+ log~
`
`[acid ]
`0.6 = log [base]
`
`106_ [acid] _ 0.25
`-
`[base] -
`1
`
`[acid]
`2.0 = log [base]
`
`10
`
`2_ [acid] _ __!QQ._
`-[base] -
`1
`% acid form= 187 x 100 = 99%
`
`Fig. 2.6. Ca lcu lation of % ionization of amobarbital. Calculation indi(cid:173)
`cates that 20% of the molecules are in the acid (or protonated) form,
`leaving 80% in the conjugate base (ionized) form .
`
`Fig. 2.7. Ca lculation of % ion ization of phenylpropanolam ine. Ca lcula(cid:173)
`tion indicat es that 99 % of the molecules are in the acid form w hich is
`the same as % ionization.
`
`phenylpropan olamine . It is very important to r ecognize
`that for a base, the pK,. refers to the co nju gate acid or
`ionized form of the compound. To thoroughly compre(cid:173)
`hend this re lationship, the student should calculate the
`percent ionization of an .acid and a base at different pH
`values.
`
`VVater Solubility of Drugs
`The solubility of a drug molecule in water greatly af(cid:173)
`fects the rou tes of administration available and its absorp(cid:173)
`tion, distribu tion and elim ination . Two key concepts to
`keep in mind when considering the water (or fat) solubil(cid:173)
`ity of a m olecule are the hydrogen bond fo rming po ten tial
`of the fun ctional groups p resent in the molecule and the
`ionization of functional groups.
`
`Hydrogen Bonds
`Each functional group capable of donating or accepting
`a hydrogen bond will contribute to the overall water solu(cid:173)
`bility of the compound. Hence, such functional groups will
`increase the hydrophilic (water loving) nature of the mol(cid:173)
`ecule. Conversely, functional groups that cannot form hy(cid:173)
`drogen bonds will n ot enhance hydrophilicity, and will ac(cid:173)
`tually contribute to the hydrophobicity (water hating) of
`the molecule. Hydrogen bonds are a special case of what
`are generally referred to as dipole-dipole bonds. Dipoles
`result from unequal sharing of electrons between atoms
`within a covalent bond. This unequal sharing of electrons
`results when two atoms involved in a covalent bond have
`significan tly differen t electronegativities. As a result, partial
`ionic character develops between the two atoms, produc-
`
`b
`
`Page 10 of 34
`
`

`
`44
`
`Fig. 2.8. Examples of hydrogen bonding between water and hypo(cid:173)
`thetica l drug molecules.
`
`ing a permanent dipole: One end of the covalent bond has
`higher electron density than the other. When two mole(cid:173)
`cules containing dipoles approach one another they align
`such that the negative end of one dipole is electrostatically
`attracted to the positive end of the other. When the posi(cid:173)
`tive end of the dipole is a hydrogen atom, this interaction
`is referred to as a hydrogen bond (or H-bond). Thus, for a hy(cid:173)
`drogen bond to occur at least one dipole must contain an
`electropositive hydrogen. The hydrogen atom must be in(cid:173)
`volved in a covalent bond with an electronegative atom
`such as oxygen (0), nitrogen (N), sulfur (S) or selenium
`(Se). Of these four elements only 0 and N contribute sig(cid:173)
`nificantly to the dipole and we will therefore only concern
`ourselves with the hydrogen bonding capability of OH and
`NH groups. This is only in reference to functional groups
`that "donate" hydrogen bonds.
`Even though the energy involved for each hydrogen
`bond is small, 1-10 kcal/mol/bond, it is the additive na(cid:173)
`ture of multiple hydrogen bonds that contributes to water
`solubility. We will see in Chapter 4 that this same bonding in(cid:173)
`teraction is also important in drug-receptor interactions. Fig(cid:173)
`ure 2.8 shows several possible hydrogen bond types that may
`occur with different organic functional groups and water. As
`a general rule, the more hydrogen_ bonds that are possible,
`
`Table 2.4. Common Organic Functional Groups
`and Their Hydrogen-Bonding Potential
`
`Functional Groups
`
`R-OH
`
`R-NH
`I
`R'
`
`R-N-R"
`I
`R'
`
`Number of Potential
`H-bonds
`
`3
`
`2
`
`3
`
`2
`
`4
`
`PART I I PRINCIPLES OF DRUG DISCOVERY
`
`the greater the water solubility of the molecule. Table 2.4
`lists several common organic functional groups and the
`number of potential hydrogen bonds for each. This table
`does not take into account the possibility of intrarrwlecular hy(cid:173)
`drogen bonds that could form. Each intramolecular hydro(cid:173)
`gen bond would decrease water solubility (and increase lipid
`solubility) since one less interaction with solvent occurs.
`
`Ionization
`In addition to the hydrogen bonding capability of a
`molecule, another type of bonding interaction plays an
`important role in determining water solubility: Ion-Dipole
`bonding. This type of bonding comes into play when one
`deals with organic salts. Ion-dipole bonds develop between
`either a cation or anion and a formal dipole such as water.
`A cation, having a deficiency in electron density, will be at(cid:173)
`tracted to regions of high electron density. When dealing
`with water, this would be the two lone pairs of electrons as(cid:173)
`sociated with the oxygen atom. An anion will associate
`with regions of low electron density or the positive end of
`the dipole. In the case of water as solvent, this would be
`the hydrogen atoms (Fig. 2.9) .
`Not all organic salts are n ecessarily very water soluble. In
`order to associate with enough water molecules to become
`soluble, the salt must be highly dissociable; i.e., the cation
`and anion must be able to separate and each interact with
`water molecules. Highly dissociable salts are those formed
`from stro