v
`
`Fnue‘s Principles of
`
`Medicinal Enemisiru
`
`FIFTH EDITION
`
`‘
`
`Page 1 of 34
`
`SENJU EXHIBIT 2156
`
`LUPIN v. SENJU
`IPR20l5—0l 100
`
`

`
`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 LlPPII\COTT WILLIAMS (3 \X/ILKINS
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`contraindications, dosages. and precautions.
`
`hinted in the Lhtitad Slam ofAmerica
`
`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.-—5Lh ed.
`.
`cm.
`Infludes index.
`ISBN 0-683-30737-1
`1. Pharmaceutical chemistry. 1. Title: Principles of medicinal chemistry. 1]. Lemlte.
`Thomas L III. Title.
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`Page 3 of 34_
`
`

`
`Medicinal chemistry is the discipline concerned with de-
`ggrmining 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-
`ties of the molecule. The term “physicochemical properties"
`refers to the influence of the organic functional groups pres-
`ent within a molecule on its acid/base properties, water sol-
`ubility, partition coeificient, crystal structure, stereochem-
`istry etc. All of these properties influence the absorption,
`distribution, metabolism and excretion (ADME) of the mol-
`
`ecule. In order to design better medicinal agents the medic-
`‘uial chemist needs to understand the relative contributions
`
`‘
`
`that each functional group makes to the overall physical
`chemical 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-
`tivity. Such studies are referred to as studies of structure-
`activity relationships i.e., what structural features of the mo]-
`ecule conuibute to, or take away from, the desired biologi-
`cal activity of the molecule of interest.
`Because of the fundamental nature of its subject matter,
`this chapter includes numerous case studies throughout
`(as boxes) and at the end. In addition, a list of study ques-
`tions at the end of—and unique to—this chapter provides
`further self-study material on the subject of drug design.
`
`run-
`
`INTRODUCTION
`
`Chemical compounds, usually derived from plants,
`I'p0'
`32.
`have been used by humans for thousands of years to alle-
`viate pain, diarrhea, infection and various other maladies.
`:28_
`,,-id Until the 19th century these “remedies” were primarily
`crude preparations of plant material whose constituents
`were unknown and the nature of the active principal (if
`any) was also unknown. The revolution in synthetic or-
`ganic chemistry during the 19th century produced a con-
`‘ certed effort toward identification of the structures of the
`active constituents of these naturally derived medicinals
`and synthesis of what were hoped to be more eflicacious
`agents. By determining the molecular structures of the ac-
`tive components of these complex mixtures it was thought
`that a better understanding of, how these components
`Worked could be elucidated.
`
`Relationship Between Molecular Structure
`Ind Biologic Activity
`Early studies of the relationship between chemical
`structure and biologic activity were conducted by Crum-
`
`Page 4 of 34
`
`Brown and Fraser (1) in 1869. They showed that many
`compounds containing tertiary amine groups became
`muscle relaxants when converted to quaternary ammo-
`nium compounds. Compounds with widely differing phar-
`macological properties such as, strychnine (a convulsant).
`morphine (an analgesic), nicotine (deterrent,
`insecti-
`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-
`
`tivity required a quaternary ammonium group within the
`chemical structure. This initial hypothesis was later dis-
`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-
`pothesis concerning chemical structure and muscle relax-
`ation was proven to be incorrect, it demonstrated the con-
`cept
`that molecular
`structure does
`influence
`the
`biological activity of chemical compounds.
`Mm the discovery by Crum-Brown and Fraser that qua-
`ternary ammonium groups could produce compounds
`with muscle relaxant properties scientists began looking
`
`N-0":
`
`X9
`
`HO
`
`'"
`
`"on
`
`i Ho
`
`\"'
`
`‘OH
`
`.
`M
`(ar7aT"ge'3i7:>
`
`N-Methylrnorphlne
`(muscle relaxant)
`
`0*?’CH3
`
`N
`
`j> [;j'P[":g Xe
`
`H30‘ CH3
`
`Nicotine_
`(Insecticide)
`
`N-Mothylnlcotine
`(muscle relaxant)
`
`H3C~N
`
`H9C.€»CH3 X9
`
`i
`
`H,oH
`
`o
`
`”
`
`l-50H
`
`0
`
`Am, Ins
`(mydgancy
`
`N-Methylatroplne
`(muscle relaxant)
`
`Fig. 2.1. Effects of methylation on biologic activity.
`
`37
`
`

`
`38
`
`PARTI /PRINCIPLES OF DRUG DISCOVERY
`
`
`
`it
`me o’\/231,,
`
`Fig. 2.2. Acetyloholine. 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 efiects. This lead to
`the postulate, which took some time to disprove, that “one
`chemical group gives one biological action." (2) Even af-
`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-
`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-
`ganisms, Ehrlich developed the concept of drug receptors
`(4). He postulated that certain "side chains” on the sur-
`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-
`ease states without producing undue harm to the organ-
`ism being treated (i.e., the patient). This concept was later
`modified by Albert (5) and is generally referred to as "se-
`lective toxicity.” Utilizing this concept Ehrlich developed
`organic arsenicals that were toxic to trypanosomes as a re-
`sult of their irreversible reaction with mercapto groups
`present on vital proteins within the organism. The forma-
`tion of As-S bonds resulted in death to the target organ-
`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 discovery of
`The “paradox" that resulted after
`acetylcholine of how one chemical group can produce two
`different biologic effects. i.e., muscle relaxation and mus-
`cle contraction, was explained by log (6) using the actions
`of acetylcholine and tubocurarine as his examples. lng hy-
`pothesizcd that both acetylcholine and tubocurarine act at
`the same receptor but that one molecule fits to the recep-
`tor in a more complementary manner and “activatcs" it.
`causing muscle contraction._]ust how this activation occurs
`
`Page 5 of 34
`
`was not elaborated upon. The larger molecule, tubocu-
`rarine, simple occupies part of the receptor and prevents
`acetylcholine, the smaller molecule, from occupying the
`receptor. Virrth both molecules the quaternary ammonium
`functional group is a common structural feature and in-
`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-
`erally larger in size than the native compound. Both com-
`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, detennines 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-
`monium or protonated tertiary ammonium group and will
`be larger than acetylcholine. Structure-activity relation-
`ships (SARS) are the underlying principle of medicinal
`chemistry. Similar molecules exert similar biological ac-
`tions in a qualitative sense. A corollary to this is that struc-
`tural elements (functional groups) within a molecule most
`often contribute in an additive manner to the physico-
`chemical properties of a molecule and therefore its bio-
`logical action. One need only peruse the structures of
`drug molecules in a particular phannacologic class to be-
`come convinced of this (e.g., histamine H. antagonists;
`histamine H, antagonists; B-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-aminobcnzoic acid
`(PABA) are shown. In 1940, Woods (7) demonstrated that
`PABA was capable of reversing the antibacterial action of
`sulfanilamide (and other sulfonarnides antibacterials) and
`that both PABA and sulfanilamide had similar steric and
`
`electronic properties. Both compounds contain acidic flinc-
`
`H.N.H
`
`H.N.H
`
`5.7 A ©
`/C
`0, .09
`
`p-Amlnobenzolc acid
`
`6.9A
`
`: :
`o 2 o
`H 9
`Sullanilamide
`
`Ionized forms of PABA and sulfanilarnide, Comparison of
`Fig. 2.3.
`distance between amino and ionized acids of oach compound. Note
`how closely sulfanilamide resembles PABA.
`
`

`
`?
`
`Cliff
`
`TER 2/ DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY
`
`39
`
`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-
`monium compounds the molecule is not electrically neu-
`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-
`ple, ciprofloxacin (Fig. 2.4) a quinolone antibiotic, con-
`tains a secondary alkyl amine and a carboxylic acid. De-
`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 diflerent 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 alley]-
`amine) is ionized. In order to be able to make this predic-
`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 pig not only indicates the relative
`acid/ base strength oforganic functional groups, but it also
`allows one to calculate, for a given pH, exactly how much
`of the molecule is in the ionized and unionized fonn.
`
`Relative Acid Strength lpK.l
`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 HCI or bases such as NaOH undergo complete dis-
`sociation in water with the equilibrium shifted completely
`to the right side as shown in equations 2.3 and 2.4:
`
`
`
`__ (:19 + H,o@
`
`Eq. 2.3
`
`HCI + H._.0
`
`Eq. 2.4
`
`Nero}! + too — Na© + one + H20
`
`However, acids and bases of intermediate or weak
`
`strength incompletely dissociate or accept a proton and
`the equilibrium lies somewhere in between. The equilib-
`rium is such that all posible species may exist. Note that
`in equations 2.3 and 2.4 water is acting as a base in one in-
`stance and as an acid in the other. Water is amphoteric, it
`may act as an acid or a base depending upon the condi-
`tions. Because we are always dealing with a dilute aqueous
`solution the strongest base that can be present is OH‘ and
`the strongest acid l-1,0". This is known as the leveling ef-
`
`U-Onaj groups with PABA containing an aromatic carboxylic
`acid and sulfanilamide an aromatic sulfonamidc. When ion-
`mg at physiological pH both compounds have a similar
`electronic configuration and the distance between the ion-
`ized acid and the weakly basic amino group is also very sim-
`gar. It should therefore be no surprise that sulfanilamide
`ads as an antagonist to PABA metabolism in bacteria.
`
`pl-IYSICOCHEIVIICAL PROPERTIES OF DRUGS
`Agid/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-
`ular weight of 200 g/mol and a dose of 20 mg this leads to
`a concentration of ~2 X 10*’ M solution. When consider-
`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-
`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 directly affect ab-
`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-
`jugate base. Similarly, when a base accepts a proton it is con-
`verted to its conjugate acid ionn (Equations 2.1 and 2.2).
`
`Eq. 2.1
`
`sq. 2.2
`
`cH,coorr + 11,0 := cH,coo9 + I-{,0©
`Acid
`Base
`Conjugate
`Conjugate
`(acetic acid)
`(water)
`base
`acid
`(acetate)
`lhydronium)
`
`+ up 3 cu,Nu,@ + 90:1
`cir,Nn.,
`Acid
`Conjugate
`Conjugate
`Base
`(mcthylaminc) (water)
`Acid
`base
`(mcthylammanium) (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-
`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-
`don 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-
`Ondary and tertiary amines. Other organic functional
`groups that act as bases are shown in Table 2.2. Again the
`
`Page 6 of 34
`
`%
`
`

`
`40
`
`PART II PRINCIPLES OF DRUG DISCOVERY
`
`Table 2.1. Common Acidic Organic Functional Groups andTheir Ionized (Coniugate Base) Forms
`
`
`
`Alkylthiol
`
`|O—H
`
`R—SH
`
`12-89
`
`Q
`O
`
`Conjugate Base
`
`Phenolate
`
`9 G
`R-§-NH0
`
`Sulfonamndate
`
`DO‘:
`0 JOL
`HA3) R"—RJLN n‘
`
`lmidate
`
`Thuo|aIe
`
`Thuophenolate
`
`N-Arvlsulfonamidate
`
`Acids
`
`Phenol
`
`pKa
`
`9—11
`
`Sulfonamide
`
`9-10
`
`lmide
`
`9-10
`
`Thiophenol
`
`9—1O
`
`N-Arylsulfonamide
`
`6-7
`
`Sulfonimide
`
`5-6
`
`Alkylcarboxylic acid
`
`Arwcarboxylic acid
`
`89
`
`R—' \‘ /
`
`ll
`O 9
`R-§-N I \
`o
`x _Fl
`
`Ow 0
`CW0 00
`R, gig. — R,s.N.J\R,
`
`Sulfonimidate
`
`9 9
`H-C-O
`
`Alkylcarboxylate
`
`C009
`
`Arylcamoxylate
`
`Sulionic acid
`
`0—1
`
`go '10
`H,s.Oe
`
`
`Suefonate
`
`Acid strength usualry incveases as one moves down the table.
`
`Page 7 of 34
`
`

`
`
`
`R 2/ DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS T0 PHARMACOLOGIC ACTIVITY
`
`41
`
`- D“ 2.2- common Basic Organic Functional Groups and Their Ionized (Conjugate Acidl Forms
`To
`Ba“
`pKa
`—
`Aiymmme
`4 5
`
`\ NHa®
`
`/
`
`Conjugate Acid
`'
`Arvlammonrum
`
`
`
`.
`
`NH
`
`R9, 2
`v
`
`Amman-C amme
`
`5-6
`
`‘I/§N
`R-—.\)
`
`(§NH®
`HQ
`
`Aromatic ammonium
`
`lmme
`
`3-4
`
`R-fi=NH
`
`A|ky|afn|neS
`
`Amidne
`
`10-11
`
`9“°
`
`10-11
`
`OIH
`
`R-NH2
`
`JNLH
`NH;
`
`Fl
`
`_ O
`Fl-C—NH
`H
`
`(9
`
`OH:
`
`Fl-NH3 69
`
`’ll~ll\l—l2 @
`NH;
`
`Fl
`
`lminium
`
`Alkylammonium
`
`Nniornium
`
`Guanidinium
`JTZ ®
`JNLH
`10-11
`Guanrdine
`NH
`Fifi
`2
`u
`NH?
`
`
`H“
`
`Table 2.3. Common Organic Functional GroupsThat Ara Considered Neutral Under Physiologic Conditions
`O
`
`.
`
`R—CH2-OH
`A”<Y| alcohol
`
`,1
`
`Fl
`
`NH2
`
`Armde
`RI
`R—rsr->0
`R’
`
`’Q_
`
`R
`Ether
`
`R’
`
`H
`
`I \ K0
`R//
`
`H.
`
`Diarylamrne
`
`/‘OK
`
`R
`
`Hr
`
`Ami” °KIde
`
`Ketone & Aldehyde
`
`Page 8 of 34
`
` j___j1g?._.j_
`
`,IL 5;
`O
`
`R
`Ester
`
`R_CEN
`
`Nitrile
`
`’S_ I
`H
`
`H
`
`Throether
`
`R.
`
`Ox ,0
`.3,
`. \ ,
`O
`H
`Sullonic acid ester
`
`‘T5’
`R-2:9-~
`
`Quaternary ammonrum
`
`53?
`
`R’
`
`‘R:
`
`0M0
`H¢S~R,
`
`Sulfoxrde
`
`Sulfone
`
`

`
`
`
`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-
`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 degree of ionization of a molb
`cule one must know the pig values of the acid and basic
`functional groups present and the pH of the environment
`to which the compound will be exposed. The Henderson-
`Hassalbach equation (Equation 2.6) can be used to calcu-
`late the percent ionization ofa compound at a given pH.
`This equation was used to calculate the major forms of
`ciprofloxacin in Figure 2.5.
`
`Eq.2.ti
`
`pK,
`
`pH t
`
`log
`
`[_a1cl form],
`[base form)
`
`The key to understanding the use of the Henderson-
`Hassalbach equation for calculating percent ioniration is to
`realize that this equation relates a constant, pK,, to the ratio
`of acid form to base fonn of the drug. Since pK., is a constant
`for any given molecule, then the ratio of acid to base will de-
`tennine the pH of the solution. Conversely, a given pH de-
`termines the ratio of acid to base. A sample calculation is
`shown in Figure 2.6 for the sedative hypnotic amobarbital.
`\Vhen dealing with a base. the student must recognize
`that the conjugate acid form is the ionized form of the
`drug. Thus, as one should expect, a base behaves in a
`manner opposite to that of an acid. Figure 2.7 shows the
`calculated percent
`ionization for
`the decongestant
`
`Fig. 2.5. Predomtnate forms of ciprofloxacin at two different locations
`within the gastrointestinal tract.
`
`fect of water. Thus, some organic functional groups that
`are considered acids or bases with respect to their chemi-
`cal reactivity do not behave as such under physiological
`conditions in aqueous solution. For example, alltyl alco-
`hols such as ethyl alcohol, are not sufficiently acidic to un-
`dergo ionization to a significant extent in aqueous solu-
`tion. Water is not sufliciently basic to remove the proton
`from the alcohol to form the ethoxide ion (Equation 2.5).
`
`__ cn,cu,o + 11.09"’
`
`ct-i,cH._.oH + up
`
`F.q 25
`
`AbsorptionIAcid-Base case
`
`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 tal<esTUMs for indigestion be-
`cause of the bad food that he eats while he is on the road.
`
`0 oW°*”°“°“
`0
`
`0
`
`.
`
`°“=
`
`'’°“‘55
`
`CH3r
`
`‘CH;
`
`0 .0 °°="
`
`cetirlzlne (knee)
`
`Glernudloe (Tlvistl
`
`Olopaudine (Pntanol)
`
`1.
`
`identify the functional groups present in Zyrtec and Tavlst 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 = 15).
`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 antlhistaminergic effect it he takes his antihistamine at the same time as he takes his
`TUMs. Provide a rationale for your answer.
`
`Page 9 of 34
`
`42
`
`nwoge"
`neutral
`
`ketone. neutral
`
`carbo licacid
`acidicxy
`
`"
`
`aryl amine. weak base
`
`
`
`alkyl amine
`basic
`
`arylamlne
`weak base
`
`Fig. 2.4. Chemical structure of crprotloxacin showing the various or-
`ganic functional groups.
`
`0
`
`N
`
`A
`
`O
`
`N
`
`G) |/\ N
`
`H-rdH
`
`Duodenum (PH ~4l
`
`(9
`
`N
`
`H-it/;'
`
`H S
`
`tomach (pH 1.0 - 3.5)
`
`

`
`l’
`
`CHApTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY
`
`Acid Base Chemistrvlcompatibility Cases
`
`The iv technician in the hospital pharmacy gets an order for a patient that includes the two drugs drawn below. She is un-
`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.
`
`Penlclllln V Potasdttm
`
`_ Penicillin 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 phosphate.
`, As originally drawn above, which of these two agents is more water-soluble? Provide a rationale 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.
`. What is the chemical consequence of mixing aqueous solutions of each drug in the same IV bag? Provide a ration-
`ale that includes an acid/base assessment.
`
`39¢
`
`o
`
`O
`
`O
`
`NNe"‘HN
`To
`
`Conjugate base
`
`‘f
`0e
`
`3356 Y0?!"
`
`Conjugate acid term
`pK, 9.4
`
`Question: At a pH of 7.4. what is the percent ionlzatlon of amobarbital?
`
`Question: What is the percent ionization of phenylpropanolamine
`at pH 7.4?
`
`A'l5W°'=
`
`5.0 = 7.4 + log agisi
`acid
`ase
`
`= log
`
`106:
`
`aegis1] = 0.25
`
`Answer:
`
`add]
`ass
`
`9.4 - 7.4+ log
`acid
`359
`
`2.0= log
`
`m2_ ag}
`1oo
`e=‘“_I
`
`'7. acid form = -9-351-331-Q1 = 30%
`
`"/oacldlorm= +8%x1oo = 99%
`
`Fig. 2.6. Calculation of % ionization of emobarbital. Calculation indi-
`cates that 20% of the molecules are in the acid (or protonated) form,
`leaving 80% in the conjugate base lzonizedl form.
`
`Fig. 2.7. Calculation of % ionization of phenylpropanolamine. Calcula—
`tion indicates that 99% of the molecules are in the acid form which is
`the same as % ionization.
`
`phcnylpropanolaminc. It is very important to recognize
`that for a base, the pK,, refers to the conjugate acid or
`ionized form of the compound. To thoroughly compre-
`hend this relationship, the student should calculate the
`percent ionization of an acid and a base at ditfcrcnt pH
`values.
`
`Water Solubility of Drugs
`The solubility of a drug molecule in water greatly af-
`ftcts the routes of adtninistranon available and its absorp-
`“On, distribution and elimination. ‘lwo key concepts to
`lteep in mind when considering the water (or fat) solubil-
`“V 0f a molecule are the hydrogen bond forming potential
`fif the functional groups present in the molecule and the
`|0ni7ation of functional groups.
`
`Hydrogen Bonds
`Each functional group capable of donating or accepting
`a hydrogen bond will contribute to the overall water solu-
`bility of the compound. Hence, such functional groups will
`increase the hydrophilic (water loving) nature of the mol-
`ecule. Conversely, functional groups that cannot form hy-
`drogcn bonds will not enhance hydrophilicity, and will ac-
`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
`
`significantly ditferent clectronegativities. As a result, partial
`ionic character develops between the two atoms, produc-
`
`Page 10 of 34
`
`§_
`
`

`
`44
`
`PART I I PRINCIPLES OF DRUG DISCOVERY
`
`
`
`,|,
`
`,
`
`‘it
`
`H.o‘.H
`'2
`H
`OM
`-'
`"
`H‘0‘“
`
`,'
`
`‘I
`o.
`
`'7
`H-0
`
`«-
`Rxkxpi
`
`Fig. 2.8. Examples of hydrogen bonding between water and hypo-
`thetical drug molecules.
`
`ing a permanent dipole: One end of the covalent bond has
`higher electron density than the other. When two mole-
`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-
`tive end of the dipole is a hydrogen atom, this interaction
`is referred to as a hydrogm band (or H-bond). Thus. for a hy-
`drogen bond to occur at least one dipole must contain an
`electropositive hydrogen. The hydrogen atom must be in-
`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-
`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-
`
`ture of multiple hydrogen bonds that contributes to water
`solubility. We will see in Chapter 4 that this same bonding in-
`teraction is also important in dmg-receptor interactions. Fig-
`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
`
`Number of Potential
`H-bonds
`
`3
`
`2
`
`3
`
`2
`
`1
`
`4
`
`R—0H
`
`0
`RJLR,
`
`H—NH,
`
`R-l;lH
`RI
`
`R-l'€—R'
`RI
`
`Page 11 of 34
`
`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 i-ntranwIecularhy-
`drogen bonds that could form. Each intramolecular hydro-
`gen bondwould 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: lon-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-
`tracted to regions of high electron density. When dealing
`with water, this would be the two lone pairs of electrons as-
`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 necessarily 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 strong acids with strong bases, weak acids with strong
`bases and strong acids with weak bases. Strong acids are hy-
`drochloric, sulfuric, nitric, perchloric and phosphoric acid.
`All other acids are considered to be weak. Sodium hydrox-
`ide and potassium hydroxide are considcred- to be strong
`bases, with all other bases classified as weak. Thus the salt of
`a carboxylic acid and alkylamine is a salt of a weak acid and
`weak base respectively, and therefore does not dissociate ap
`preciable. This salt would not be very water soluble. Some
`examples of common organic salts used in pharmaceutical
`preparations are provided in Figure 2.10.
`When dealing with the water solubility of ionized
`molecules one must also consider the possibility of in-
`tramolecular ionic bonding. Compounds with ionimble
`functional groups that produce opposite charges have
`the potential to interact with each other rather than wa-
`ter molecules. When this occurs such compounds often
`become very insoluble in water. A classic example is the
`amino acid tyrosine (Fig. 2.11). Tyrosine contains three
`very polar functional groups with two of these (the alkyl-
`amine and carboxylic acid) being capable of ionization.
`depending on the pH of the solution. The phenolic hy-
`
`2+
`are
`0%"
`
`Fig. 2.9. Examples of ion-dipole bonds.
`
`

`
`/ DRUG DESl§_N AND RELATIONSHIP OF FUNCTIONAL GROUPSTO PHARMACOLOGIC ACTIVITY
`
`Fig. 2.11. Functional groups present in tyrosine. their hydrogen-bond-
`ing potential, and pK, values.
`
`droxyl is also ionizable. but it doesn't contribute under
`the conditions most often encountered in pharmaceuti-
`cal formulations or physiologic conditions. Because of
`the