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`Medicinal
`
`Chemistry
`
`SEVENTH EDITION
`
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`Li .i 1iist
`SEVENTH EDITION
`
`THOMAS
`
`Edited By
`LEMKE PHD
`Professor Emeritus
`
`College of Pharmacy
`University of Houston
`Houston Texas
`
`Associate Editors
`
`VICTORIA
`
`ROCHE PHD
`Professor ofPharmacy Sciences
`School ofPharmacy and Health Professions
`
`Creihton University
`Omaha Nebraska
`
`DAVHD
`
`WILLIAMS PHD
`Professor Emeritus of Chemistry
`Massachusetts College ofPharmacy and
`Health Sciences
`
`Boston Massachusetts
`
`WILLIAM ZITO PHD
`Professor Pharmaceutical Sciences
`College ofPharmacy and Allied Health
`Professions
`
`St John University
`amaica New York
`
`Wolters Kiuwer Lippincott Williams Wilkins
`Hea
`
`Battimore New York
`PhiLadelphia
`Buenos Aires Hong Kong
`
`Sydney
`
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`
`Tokyo
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`Seventh Edition
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`Library of Congress Cataloging-in-Publication Data
`edited by Thomas
`Foyes principles of medicinal chemistry
`7th ed
`Roche William Zito
`editors Victoria
`cm
`Principles of medicinal chemistry
`references
`Includes bibliographical
`ISBN 978
`60913 345-0
`II Lemke Thomas
`Foye William
`chemistry
`
`III Williams David
`
`and indexes
`
`616.0756
`
`Chemistry Pharmaceutical QV 744
`dc23
`
`Lemke David
`
`Williams
`
`associate
`
`1938- IV Title Principles of medicinal
`
`2011036313
`
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`to ensure that drug selection
`dosage set forth in this text are in accordance with the current recommendations and practice at
`the
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`flow of information relating to drug therapy and drug reactions the reader is urged to check
`constant
`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
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`
`ontei
`
`Preface
`Contributors
`
`vii
`
`xi
`
`Reviewers
`
`xv
`
`History and Evolution of Medicinal
`Chemistry
`NEUMEYER
`
`JOHN
`
`PART
`
`Principles ofDrug Discovery
`
`Chapter
`
`Chapter
`
`hapter
`
`Drug Discovery from Natural
`Products
`13
`DOUGLAS KINGHORN
`
`Drug Design and Relationship of
`Functional Groups to Pharmacologic
`29
`Activity
`ZAVOD AND JAMES
`ROBIN
`
`KNITTEL
`
`and Biopharmaceutical
`Physicochemical
`Properties of Drug Substances
`and Pharmacokinetics
`61
`SUNIL
`
`JAMBHEKAR
`
`Chapter
`
`Drug Metabolism 106
`WILLIAMS
`DAVID
`
`hapter
`
`hapter
`
`hapter
`
`hapter
`
`Membrane Drug Transporters
`MORRIS AND BRIDGFT
`MARILYN
`
`191
`MORSF
`
`Pharmaceutical Biotechnology
`TALELE MARC GILLESPIE
`TANAJI
`AND VIJAYA
`KORLIPARA
`
`210
`
`Receptors as Targets br Drug
`263
`Discovery
`JOHNSON AND TIMOTHY
`DAVID
`
`MAHER
`
`Drug Discovery Through Enzyme
`283
`Inhibition
`STEPHEN KERR
`
`PART II Drug Receptors Affecting
`Neurotransmission and Enzymes as Catalytic
`Receptors
`
`Chapter
`
`Drugs Mfecting Cholinergic
`309
`Neurotransmission
`
`KIM FlEER
`
`Chapter 10
`
`Adrenergic Receptors and Drugs Mfecting
`340
`Adrenergic Neurotransmission
`ROBERT
`GRIFFITH
`
`Chapter
`
`Serotonin Receptors and Drugs Mfecting
`365
`Serotonergic Neurotransinission
`GLENNON AND
`RICHARD
`MkLGORZATA DUKAT
`
`Chapter 12
`
`Amino Acid Neurotransmitters in the
`Centri1 Nervous System 397
`TIMOTHY
`MAHER
`
`PART III Pharmacodynamic Agents
`Drugs Affecting Central Nervous System
`Section
`
`Chapter 13
`
`Drugs Used to Treat Neuromuscular
`Disorders Antiparkinsonian
`and Spasmolytic Agents
`419
`RAYMOND
`BOOTH
`
`Chapter 14
`
`Antipsychotic and Anxiolytic Drugs
`RAYMOND
`BOOTH
`
`448
`
`Chapter
`
`15
`
`Sedative-Hypnotics
`MON IRI
`NADER
`
`485
`
`Chapter 16
`
`Anesthetic Agents General and Local
`Anesthetics
`508
`TIMOTHY
`MAHER
`
`Chapter 17
`
`Antiseizure Drugs
`BARBARA LEDUC
`
`540
`
`xvii
`
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`
`xviii
`
`CONTENTS
`
`Chapter
`
`18
`
`Antidepressants
`DAVID
`WILLIAMS
`
`570
`
`Chapter 19
`
`Hallucinogens Stimulants and Related
`Drugs of Abuse nd Their Ther2pelitic
`632
`GLEN NON
`
`Potential
`RICHARD
`
`Chapter
`
`658
`Central Analgesics
`WILLIAMS VICTORIA
`DAVID
`AND EDWARD
`ROCHE
`
`ROCHE
`
`Section
`
`Drugs Affecting the Cardiovascular System
`
`Chapter
`
`21
`
`Cardiac Agents Cardiac Glycosides
`Antianginal and Antiarrhythmic
`700
`Drugs
`AHMED
`MEHANNA
`
`Chapter 32
`
`Antihistamines and Related Antiallergic
`and Antiulcer Agents
`1045
`WENDEL
`NELSON
`
`Section
`
`Chemotherapeutic Agents
`
`Chapter 33
`
`Antibiotics and Antimicrobial
`1073
`GENTRY
`
`Agents
`ELMER
`
`Chapter 34
`
`Antiparasitic Agents
`THOMAS
`LEMKE
`
`1125
`
`Chapter 35
`
`Antifungal Agents
`ROBERT
`GRIFFITH
`
`1158
`
`Chapter 36
`
`Antimycobacterial Agents
`THOMAS
`LEMKE
`
`1175
`
`Chapter 22
`
`728
`Diuretics
`HARVISON AND GARY
`PETER
`
`RAN KIN
`
`Chapter 37
`
`Cancer and Chemotherapy
`ROCHE
`VICTORIA
`
`1199
`
`Chapter 23
`
`Agents Mfecting the Renin-Angiotensin
`Pathway and Calcium Blockers
`747
`MARC HARROLD
`
`Chapter 38
`
`Antiviral Agents and Protease
`1267
`Inhibitors
`WOSTER
`
`PATRICK
`
`Chapter 24
`
`Central and Peripheral Sympatholytics
`and Vasodilators
`781
`DAVID
`WILLIAMS
`
`Chapter 25
`
`Antihyperlipoproteinemics
`of Cholesterol Biosynthesis
`MARC HARROLD
`
`and Inhibitors
`815
`
`pter 26
`
`Antithrombotics Thrombolytics
`Antiplatelets and Coagulants
`MATTHIASC IIJ
`
`841
`
`Drugs Affecting the Hormonal Systems
`
`Insulin and Drugs Used to Treat
`Tabetes
`877
`WILLIAM ZITO
`
`enocorticoids
`NE
`MILLER ROBERT
`\MES
`DALTON
`
`907
`
`BRUEGGEMEIER
`
`PART IV Disease State Management
`
`Chapter 39
`
`Asthma and Chronic
`Pulmonary Disease
`WILLIAM ZITO
`
`Obstructive
`
`1309
`
`Chapter 40
`
`Mens Health
`1346
`DUANE
`MILLER ROBERT
`AND JAMES
`DALTON
`
`Chapter 41 Womens Health
`ZAVOD
`ROBIN
`
`1386
`
`BRUEGGEMEIER
`
`Chapter 42
`
`Nutrition and Obesity
`1434
`LEMKE AND DAVID
`THOMAS
`
`WILLIAMS
`
`Appendix
`
`pK and CLogP Values for Some Drugs
`and pK Values for Miscellaneous Organic
`Acids and Bases
`1469
`
`Appendix
`
`pH Values for Tissue Fluids
`
`1479
`
`Function and Thyroid Drugs
`IJAMALI
`
`943
`
`Drug Index
`Index
`Subject
`
`1481
`
`1489
`
`Chapter 30
`
`Calcium Homeostasis
`ZAVOD
`ROBIN
`
`964
`
`Section
`
`Drugs Affecting the Immune System
`
`Chapter 31
`
`Nonsteroidal Anti-Inflammatory Drugs
`RONALD BORNE MARK LEVI
`AND NORMAN WILSON
`
`987
`
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`
`cti
`
`Acti
`
`ND JAMES
`
`bbreviations
`
`hydrochloric acid
`
`intravenous
`
`molecular weight
`aOH sodium hydroxide
`
`PABA
`aminobenzoic acid
`QSAR quantitative structureactivity
`relationship
`
`SAR structureactivity relationship
`USP U.S Pharmacopeia
`
`edicinal chemistry is an interdisciplinary science at
`intersection of organic chemistry biochemistry bio
`ganic chemistry computational chemistry pharma
`ology pharmacognosy molecular biology and physical
`ilemistry This branch of chemistry is involved with the
`tntificatiun design synthesis and develupmeni of 1itw
`rugs that are safe and suitable for therapeutic use in
`umans and pets It also includes the study of marketed
`ugs their biologic properties and their quantitative
`uctureactivity relationships QSARs
`Medicinal chemistry studies how chemical structure
`fluences biologic activity As such it
`is necessary to
`derstand not only the mechanism by which
`drug
`erts its effect but also how the molecular and physico
`emical properties of the molecule influence the drugs
`armacokinetics absorption distribution metabolism
`xicity and elimination and pharmacodynamics
`what
`drug does to the body The term physicochemical
`operties refers to how the functional groups present
`wt ilin
`molecule influence its acidbase properties
`ater snluhility partitinn cnefflcient crystal structure ste
`eochemistry and ability to interact with biologic systems
`and receptor sites
`such as enzyme active sites Chapter
`
`To design better medicinal agents the rela
`Chapter
`tive contribution that each functional group i.e pharma
`cophore makes to the overall physicochemical properties
`the molecule must be evaluated Studies of this type
`of
`involve modification of the molecule in
`systematic fash
`dtitrmination of how thest changcs
`ion followtd by
`affect biologic activity Such
`studies are referred to as
`relationships SARsthat is the rela
`structureactivity
`tionship of how structural
`features of the molecule con-
`tribute to or take away from the desired biologic activity
`Because of the foundational nature of the content of
`there are numerous case studies presented
`this chapter
`the chapter as boxes as well as at the end
`throughout
`In addition
`the conclusion
`list of study questions at
`ofand unique tothis chapter provides further self-
`study material related to the subject of medicinal chem
`istry drug design
`
`NTRODUCTION
`
`Chemical cnmpoiinds usually derived frnm plants and
`have been used by humans for
`other natural sources
`thousands of years to alleviate pain diarrhea infection
`
`29
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`
`30
`
`PART
`
`PRINCIPLES OF DRUG DISCOVERY
`
`and various other maladies Until
`the 19th century
`these remedies were primarily crude preparations of
`plant material of unknown constitution The revolution
`in synthetic organic chemistry during the 19th century
`concerted effort
`produced
`toward identification of the
`structures of the active
`constituents of these naturally
`derived medicinals and synthesis of what were hoped to
`be more efficacious agents By determining the molecu
`lar structures of the active components of these complex
`mixtures it was thought
`better iinderst2nding of
`that
`how these components worked could be elucidated
`
`BETWEEN MOLECULAR
`RELATIONSHIP
`STRUCTURE AND BIOLOGIC ACTIVITY
`
`Early studies of the relationship between chemical struc
`ture and biologic activity were conducted by Crum-Brown
`and Fraser
`in 1869 They demonstrated that many
`containing tertiary amine groups exhibited
`compounds
`activity as muscle relaxants when converted to quaternary
`ammonium compounds Molecules with widely differing
`pharmacologic properties such as strychnine
`convul
`sant morphine an analgesic nicotine
`deterrent
`and atropine an anticholinergic
`could
`insecticide
`to muscle relaxants with properties simi
`be converted
`to those of tubocurarine when methylated Fig 2.1
`lar
`that mus
`Crum-Brown and Fraser
`therefore concluded
`cle relaxant activity required the presence of
`quater
`nary ammonium group within the structure This initial
`hypothesis was later disproven by the discovery ofthe natu
`ral neurotransmitter and activator of muscle contraction
`acetylcholine Fig 2.2 Even though Crum-Brown and
`Frasers initial hypothesis that related chemical structure
`it demon-
`with action as muscle relaxant was incorrect
`that molecular structure influences
`strated the concept
`the biologic activity of chemical entities and that altera
`tions in structure produce changes in biologic action
`With the discovery by Crum-Brown and Fraser
`that
`quaternary ammonium groups could produce molecules
`with muscle relaxant properties scientists began to look
`for other functional groups that produce specific bio
`logic responses At this time it was thought
`that specific
`chemical groups or nuclei rings were responsible for
`specific biologic effects This led to the postulate that
`took some time to disprove that one chemical group
`Even aftei
`gives unt biological actioii
`the discovei
`by Loewi and Navrati
`of acetylcholine
`which effec
`tively dispensed with Crum-Brown and Frasers concept
`of all quaternary ammonium compounds being muscle
`relaxants this was still considered to be dogma and took
`long time to refute
`
`SELECTIVITY OF DRUG ACTION AND DRUG
`RECEPTORS
`
`Although the structures ofmany drugs or xeiiobiotics
`at least their functional group composition were known
`at the start of the 20th century how these compounds
`
`H3CO
`
`H3H
`
`çO \/
`
`OH
`
`CH3O
`
`Tubocurarine
`muscle relaxant
`
`201
`
`OH3
`
`HOH
`
`Morphine
`analgesic
`
`.QLN CH3
`
`Nicotine
`
`insecticide
`
`H3ON
`
`N-Methylmorphine
`muscle relaxant
`
`LN H3C 0H3
`
`N-Methylnicotine
`muscle relaxant
`
`Atropine
`mydriatic
`
`N-Methylatropine
`muscle relaxant
`
`HGURE
`
`Effects of methylation on biologic activity
`
`mystery Using his obser
`exerted their effects was still
`vations with regard to the staining behavior of micro-
`the concept of drug
`organisms Ehrlich
`developed
`receptors He postulated that certain side chains on the
`surfaces of cells were complementary to the dyes or
`drug and suggested thai
`the two could tlieiefore intei
`In the case of antimicrobial com
`act with one another
`pounds interaction of the chemical with the cell surface
`side chains produced
`toxic effect This concept was
`the first description of what
`later became known as the
`for explaining the biologic action
`receptor hypothesis
`of chemical entities Ehrlich also discussed selectivity
`
`OH3
`
`H30 OCH3
`
`FiGURE 22
`
`Acetylcholine
`
`neurotransriitter and muscle relaxant
`
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`
`CHAPTER 2/ DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY
`
`31
`
`of drug action via the concept of magic bullet He
`this selectivity permitted eradication of
`suggested that
`disease states without significant harm coming to the
`organism being treated i.e the patient This was later
`and today is referred to as selec
`riiodified by Albert
`tive toxicity An example of poor selectivity was demon-
`strated when Ehrlich developed organic arsenicals that
`result of their irrevers
`were toxic to trypanosomes as
`ible reaction with thiol groups -SH on vital proteins
`The formation of AsS bonds resulted in death to the
`target organism Unfortunately these compounds were
`toxic not only to the target organism but also to the host
`once certain blood levels of arsenic were achieved
`The paradox that
`the discovery of
`resulted after
`acetylcholinehow one chemical
`group can produce
`two different biologic effects i.e muscle relaxation and
`muscle contractionwas
`using the
`explained by Ing
`actions of acetylcholine and tubocurarine as his examples
`that both acetyl
`see also Chapter
`Ing hypothesized
`choline and tubocurarine act at
`the same receptor but
`that one molecule fits to the receptor in more comple
`mentary manner and activates it causing muscle con-
`traction Ing did not elaborate just how this activation
`occurred The blocking effect of the larger molecule
`tubocurarine
`of
`could be explained by its occupation
`part of the receptor
`thereby preventing acetylcholine
`the smaller molecule from interacting with the receptor
`With both molecules the quaternary ammonium func
`common structural
`feature and inter-
`tional group is
`acts with the same region of the receptor
`If one closely
`examines the structures of other molecules with opposing
`effects on the same pharmacologic system this appears to
`common theme Molecules that block the effects of
`be
`such as norepinephrine his-
`natural neurotransmitters
`tamine dopamine or serotonin for example are called
`antagonists and are usually larger in size than the native
`compound which is not the case for antagonists of pep-
`tide neurotransmitters and hormones such as cholecysto
`kinin melanocortin or substance
`Antagonists to these
`peptide molecules are usually smaller in size However
`the type of neurotransmitter
`regardless of
`biogenic
`amine or peptide both agonists and antagonists share
`common structural
`features with the neurotransmitter
`to the con-
`they influence This provides support
`that
`cept that the structure of molecule its composition and
`arrangement of functional groups determines the type
`i.e SAR For
`of pharmacologic effect
`that it possesses
`example compounds that are muscle relaxants that act
`via the cholinergic nervous system possess
`quaternary
`ammonium or protonated tertiary ammonium group and
`are larger than acetylcholine
`compare acetylcholine
`in
`Fig 2.2 with tubocurarine in Fig 2.1
`SARs are the underlying principle of medicinal chem
`istry Similar molecules exert similar biologic actions in
`corollary to this is that structural ele
`qualitative sense
`ments functional groups within molecule most often
`contribute in an additive manner to the physicochemical
`properties of molecule and therefore to its biologic
`
`action One need only peruse the structures of drug
`molecules in particular pharmacologic class to become
`convinced e.g histamine H1 antagonists histamine H2
`In the quest for
`antagonists f3-adrenergic antagonists
`better medicinal agents drugs it must be determined
`which functional groups within
`specific structure are
`important for its pharmacologic activity and how these
`groups can be modified to produce more potent more
`selective and safer compounds
`An example of how different
`functional groups can
`yield chemical entities with similar physicochemical
`properties is demonstrated by the sulfanilamide antibi
`otics In Figure 2.3 the structures of sulfanilamide and
`p-aminobenzoic acid PABA are shown In 1940 Woods
`demonstrated that PARA reverses the antibacterial
`action of sulfanilamide and other sulfonamide-based
`and that both PABA and sulfanilamide
`antibacterials
`have similar steric and electronic properties Both mol
`ecules contain acidic functional groups with PABA con-
`taming an aromatic carboxylic acid and sulfanilamide an
`aromatic sulfonamide When ionized at physiologic pH
`both compounds have
`similar electronic configuration
`and the distance between the ionized acid and the weakly
`basic amino group is also very similar It should be no
`surprise that sulfanilamide acts as an antagonist to PABA
`metabolism in bacteria
`
`Biologic Targets for Drug Action
`In order for drug molecules to exhibit their pharmaco
`logic activity they must interact with
`biologic target
`receptor enzyme nucleic acid or excitable
`typically
`membrane or other biopolymer These
`interactions
`occur between the functional groups found in the drug
`molecule and those found within each biologic target
`The relative fit of each drug molecule with its target is
`number of physicochemical
`function of
`properties
`including acidbase chemistry and related ionization
`functional group shape and size and three-dimensional
`spatial orientation The quality of this fit
`has
`direct
`impact on the biologic response produced
`In this
`are discussed
`functional group characteristics
`chapter
`as means to better understand overall drug molecule
`absorption distribution metabolism and excretion as
`interaction with
`well as potential
`biologic target
`
`6.9A
`
`oso
`
`p-Aminobenzoic acid
`
`Sulfanilamide
`
`acid PABA and
`FIGURE 2.3
`Ionized forms ofp-aminobenzoic
`between amine and
`sulfanilamide with comparison of the distance
`ionized acids of each compound Note how closely sulfanilamide
`resembles PABA
`
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`
`32
`
`PART
`
`PRINCIPLES OF DRUG DISCOVERY
`
`PHYSICOCHEMICAL PROPERTIES OF DRUGS
`
`AcidBase Properties
`The human body is 70 to 75% water which amounts to
`160-lb 73-kg
`of water
`approximately 51 to 55
`for
`individual For an average drug molecule with molecu
`dose of 20 mg this leads
`lar weight of 200 g/mol and
`solution concentration of approximately
`10
`to
`riM When
`considering the solution behavior
`drug within the body we are dealing with
`of
`dilute
`acidbase
`solution for which the Brônsted-Lowry
`theory is most appropriate
`to explain and predict
`acidbase behavior This is
`very important concept
`in medicinal chemistry because the acidbase proper-
`direct effect on absorp
`ties of drug molecules have
`cxci etioji aiid compatibility with other drugs iii
`tioii
`solution According to the Brônsted-Lowry Theory an
`acid is any substance capable of yielding
`proton
`and base is any substance capable of accepting
`proton When an acid gives up
`base it
`proton to
`converted to its conjugate base Similarly when
`base
`to its conjugate acid
`is converted
`proton it
`accepts
`Eqs 2.1 and 2.2
`
`is
`
`Eq 2.1
`
`CH3COOH
`Acid
`
`H20
`Base
`
`CH3COO
`Conjugate
`
`H3O
`Conjugate
`
`acetic acid
`
`water
`
`Base
`
`Acid
`
`acetate
`
`hydronium ion
`
`Eq
`
`CH3NH3
`CH3NH2
`H20
`Base
`Acid
`Conjugate
`methylamine water
`Acid
`methylammionium ion
`
`eOH
`
`Conjugate
`Base
`
`hydroxide ion
`
`Note that when an acidic functional group loses its
`proton often referred to as having undergone dissocia
`is left with an extra electron and becomes nega
`tion it
`tively charged This is the ionized form of the acid The
`ability of the ionized functional group to participate in an
`ion-dipole interaction with water see the Water Solubility
`enhances its water solubility Many
`of Drugs section
`functional groups behave as acids Table 2.1 The ability
`to recognize these functional groups and their relative
`acid strengths helps to predict absorption distribution
`excretion and potential
`incompatibilities between drugs
`When
`basic functional group is converted
`to the
`ton becomes ionized
`corresponding conjugate acid it
`In this instance however the functional group becomes
`positively charged due to the extra proton Most drugs
`that contain basic functional groups contain primary
`secondary and tertiary amines or imino amines such
`as guanidines and amidines Other functional groups
`that are basic are shown in Table 2.2 As with the acidic
`to become familiar with these
`groups it
`is important
`functional groups and their relative strengths
`Functional groups that cannot give up or accept
`pro-
`ton are considered to be neutral or nonelectrolytes
`to their acidbase properties Common
`with respect
`
`ketone neutral
`
`halogen
`neutral
`
`aryl amine
`weak base
`
`alkyl amine
`basic
`
`carboxylic acid
`
`aryl amine weak base
`
`FIGURE 2.4 Chemical structure of ciprofloxacin showing the van-
`ous organic functional groups
`
`groups are shown
`neutral
`functional
`in Table 2.3
`uaternary ammonium compounds are neither acidic
`nor basic and are not electrically neutral Additional
`information about the acidbase properties of the func
`tional groups listed in Tables 2.1 through 2.3 can be
`and Lemke 10 Review of func
`found in Gennaro
`tional groups and their acidbase properties can also
`be found at www.duq.edu/pharmacy/faculty/harrold/
`basic-concepts-in-medicinal-chemistry.cfm
`molecule can
`contain multiple functional groups
`with acidbase properties and therefore can
`possess
`both acidic and basic character For example ciproflox
`acm Fig 2.4
`antibacterial agent
`fluoroquinolone
`contains
`secondary alkylamine two tertiary arylamines
`aniline-like amines and
`carboxylic acid The two aryl
`amines are weakly basic and therefore do not contribute
`significantly to the acidbase properties of ciprofloxacin
`under physiologic conditions Depending on the pH of
`the physiologic environment
`this molecule will either
`donate
`proton secondary alkylamine
`proton
`accept
`carboxylic acid or both Thus it
`is described as ampho
`teric both acidic and basic in nature Figure 2.5 shows
`the acidbase behavior of ciprofloxacin in two different
`given pH e.g pH 1.0 to
`environments Note that at
`3.5 only one of the functional groups the alkylamine
`is significantly ionized To be able to make this predic
`tion an appreciation for the relative acidbase strength
`ofboth the acidic and basic functional groups is required
`Thus one needs to know which acidic or basic functional
`group within molecule containing multiple functional
`groups is the strongest and which acidic or basic func
`tional group is the weakest The concept of pK not only
`describes relative acidbase strength of functional groups
`
`NXH-NJ
`
`H-N
`
`Stomach pH .03.5
`
`Colon pH 5.67
`
`FIGURE 2.5
`Predominate forms of ciprofloxacin at two different
`locations within the gastrointestinal
`
`tract
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2126 - 10/38
`
`

`
`CHAPTER
`
`DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY
`
`Acid strength increases as one moves down the table
`
`given pH the rela
`but also allows one to calculate for
`tive percentages of the ionized and un-ionized forms of
`the drug As stated earlier this helps to predict
`relative
`water solubility absorption and excretion for
`compound
`
`given
`
`Relative Acid Strength PKa
`Strong acids and bases coilipletely doiiate dissociate
`or accept
`proton in aqueous solution to produce their
`respective conjugate bases and acids For example mm-
`eral acids such as hydrochloric acid HC1 or bases such
`as sodium hydroxide NaOH undergo 100% dissocia
`tion in water with the equilibrium between the ionized
`and un-ionized forms shifted completely to the right
`ionized as shown in Equations 2.3 and 2.4
`
`Eq 2.3
`
`HC1 H20
`
`Cl H3O
`
`Eq 2.4
`
`NaOH H20
`
`Na OH H20
`
`Acids and bases of intermediate or weak strength
`however
`incompletely donate dissociate or accept
`proton and the equilibrium between the ionized and
`un-ionized forms lies somewhere
`in the middle such
`that all possible species can exist at any given time Note
`in Equations 2.3 and 2.4 water acts as
`base in
`that
`one instance and as an acid in the other Water
`is there-
`fore amphotericthat
`base
`is it can act as an acid or
`depending on the prcvailing pH of the solution From
`physiologic perspective drug molecules are always
`dilute aqueous solution The strongest base
`present as
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2126 - 11/38
`
`

`
`34
`
`PART
`
`PRINCIPLES OF DRUG DISCOVERY
`
`TABLE
`
`Common Basic Organic Functional Groups and Their Ionized Conjugate Acid Forms
`
`is OH and the strongest acid is H3O
`that is present
`This is known as the leveling effect of water Thus
`some functional groups that have acidic or basic charac
`ter do not behave as such under physiologic conditions
`in aqueous solution For example alkyl alcohols such
`1s ethyl 1eo1io1 are not sufficiently acidic to hecnme
`significantly ionized in an aqueous solution at
`physi
`ologically pH Water
`is not sufficiently basic to remove
`the proton from ethyl alcohol
`to form the ethoxide ion
`
`Eq 2.5 Therefore under phsiologic conditions alco
`to acidbase properties
`hols are neutral with respect
`
`Eq 2.5
`
`CH3CHOH HCH3CH2O H3O
`
`Predicting the Degree of onization of Molecule
`and or basic func
`there are acidic
`By knowing if
`in molecule one can predict
`tional groups present
`
`TABLE
`
`Common Organic Functional Groups That are Considered Neutral UnderPhysiologic Condutons
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2126 - 12/38
`
`

`
`CHAPTER 2/ DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY
`
`35
`
`OO OO
`
`HNyNH
`
`HNyN
`
`OO
`
`HN
`
`Acid form
`
`PKa8.O
`
`Conjugate base
`
`Question At
`
`pH of 7.4 what
`amobarbital
`
`is the percent
`
`ionization of
`
`Answer
`
`8.0
`
`7.4
`
`log
`
`0.6 log
`
`1006
`
`3.98
`
`acid form
`
`3.98
`
`00
`
`4.98
`
`FIGURE 2.6
`ionization of amobarbital
`Calculation of percent
`Calculation indicates that 8o% of the molecules are in the acid
`or protonated form leaving 20% in the conjugate base ionized
`form
`
`as
`
`result of an unequal sharing of electrons between
`covalent bond This unequal shar
`the two atoms within
`ing of electrons only occurs when these two atoms have
`significantly different electronegativities When
`per-
`manent dipole is present
`partial charge is associated
`
`OH
`
`NH2
`
`11_%1_L
`CH3
`
`Base form
`
`OH
`
`NH3
`
`ç%1
`
`CH3
`
`Conjugate acid form
`PKa9.4
`
`Question What
`is the
`pH 7.4
`
`ionization of phenylpropanolamine at
`
`Answer
`
`9.4
`
`7.4
`
`log
`
`log
`
`2.0
`
`02
`
`00
`
`1x011
`
`ionization
`
`FIGURE 2.7
`ionization of phenylpropanol
`Calculation of percent
`amine Calculation indicates that 99% of the molecules are in the
`acid form which is the same as the percent ionization
`
`whether molecule is going to be predominantly ion-
`given pH To be able to quanti
`ized or un-ionized at
`the degree of ionization of molecule
`tatively predict
`the pK values of each of the acidic and basic func
`tional groups pi eseiit and the pH of
`the environ-
`in which the molecule will be located must be
`ment
`known The magnitude of the pK value is measure
`of relative acid or base strength and the Henderson-
`Hasselbalch equation Eq 2.6 can be used to calculate
`given pH
`compound at
`ionization of
`the percent
`this equation was used to calculate the major forms of
`ciprofloxacin in Fig 2.5
`
`Eq 2.6
`
`PKa
`
`pH log
`
`form
`form
`
`The key to understanding the use of the Henderson-
`Hasselbalch equation for calculating percent
`ionization
`constant pK to
`is to realize that this equation relates
`the ratio of the acidic form of
`functional group to its
`conjugate base form and conversely the conjugate acid
`form to its base Because pK is
`constant
`for any given
`functional group the ratio of acid to conjugate base or
`conjugate acid to base will determine the pH of the solu
`sample calculation is shown in Figure 2.6 for the
`tion
`sedative hypnotic amobarbital
`When dealing with
`basic functional group one
`must recognize the conjugate
`acid represents the ion-
`ized form of the functional group Figure 2.7 shows
`ionization for the decongestant
`the calculated percent
`phenylpropanolamine
`to under-
`is very important
`base the p1 refers to the conjugate
`stand that for
`acid or ionized form of the compound To thoroughly
`the percent
`comprehend this relationship calculate
`group and
`ionization of an acidic functional
`basic
`functional group at different pH values and carefully
`observe the trend
`
`It
`
`Water Solubility of Drugs
`The solubility of di ug molecule iii watei gi eatly affects
`the routes of administration that are available as well as
`its absorption distribution and elimination Two key
`concepts to keep in mind when considering the water or
`fat solubility of molecule are the potential
`for hydro
`gen bond formation and ionization of one or more func
`tional groups within the molecule
`
`Hydrogen Bonds
`Each functional group capable of donating or accepting
`hydrogen bond contributes to the overall water solu
`bility of the compound and increases the hydrophilic
`water-loving nature of the molecule Conversely func
`form hydrogen bonds do not
`tional groups that cannot
`enhance hydrophilicity and will contribute to the hydro
`phobic water-fearing nature ofthe molecule Hydrogen
`bonds are
`special case ofwhat are usually referred to as
`dipoledipole interactions
`permanent dipole occurs
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2126 - 13/38
`
`

`
`36
`
`PART
`
`PRINCIPLES OF DRUG DISCOVERY
`
`into the pharmacy com
`long-distance truck driver comes
`plaining of seasonal allergies He asks you to recommend an
`that will act as an antihistamine but that will not cause
`agent
`drowsiness He regularly takes TUMS for indigestion due to the
`bad food that he eats while on the road
`
`The intravenoLis
`
`IV technician in the hospital pharmacy gets
`the two drugs drawn below
`an order for
`that includes
`patient
`She is unsure ifshe can mix the two drugs together in the same IV
`bag and is not certain how water soluble the agents are
`
`OCOOH
`
`I__
`
`cS
`
`Cetirizine Zyrtec
`
`Clemastine Tavist
`
`CICOOH
`
`Olopatadine