03 Sar Pharmacophore Identification Drug Optimization
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STRUCTURE-ACTIVITY RELATIONSHIP, AND DRUG OPTIMIZATION STRATEGIES
PHARMACEUTICAL CHEMISTRY 129AY 2010-2011
OBJECTIVES
At the end the student should be able to:
Know the concept of structure-activity relationships and pharmacohphores;
Know the different design strategies employed to improve the overall pharmacodynamic, pharmacokinetic and toxicity profile of a drug;
Understand how these design strategies render the drugs safer and more effective;
Appreciate the efforts of medicinal chemists in giving us insight on the strategies in designing drugs to make them safer and more effective.
STRUCTURE-ACTIVITY RELATIONSHIPS
STRUCTURE ACTIVITY RELATIONSHIPS (SAR)
Identify which functional groups are important for binding and/or activity
AIM FOR STUDYING SARS
STUDYING SAR
Target
Lead Compound
X-ray crystallography
Crystallized structure
In silico analysis
Computer generated analogue
Lab Synthesis of analogues
(Combinatorial Chemistry)
In vivo
Crystal structure not
possible
In vitro
Active in vivo and in vitro
Allows identification of important groups involved in
binding
Allows identification of the pharmacophore
Gives information on the modifications that improves binding and pharmacokinetic
profile
NOTES ON ANALOGUES
Modifications may disrupt binding by electronic/ steric effect
Easiest to make are those made from lead compound
Possible modifications may depend on other groups present
Some may have to be made by a full synthesis
HBD
X
Binding site
X= N or O
OH
Drug
O
H
Drug
X
Binding site
H
HBA
ALCOHOLS AND PHENOLS
POSSIBLE BINDING INTERACTIONS
POSSIBLE ANALOGUES
H-Bonding
R OH
Ether
R OMeCH3I
EsterCH3COCl
RO
O
CH3
AlkaneCH3SO2Cl
R SO
O
CH3
O
LiAlH4R H
Example: ether
X
Binding site
X= N or OX
Binding site
H
No interaction as HBD
No interaction as HBA
steric shield
OCH3
Ether analogue
OCH3
Ether analogue
ALCOHOLS AND PHENOLS
• Increased resistance to metabolism• Decreased excretion• Increased absorption
POSSIBLE EFFECT OF ANALOGUE IN BINDING
POSSIBLE EFFECTS ON PHARMACOKINETIC PROFILE
POSSIBLE EFFECT OF ANALOGUES ON BINDING
ALCOHOLS AND PHENOLS
Example: ester
X= N or OX
Binding site
H
Electronic factor Steric Factor
steric shield
X
Binding site
H
OC
Ester analogue
CH3
O
OC
CH3
O
+ OC
Ester analogue
CH3
O
• Increased susceptibility to metabolism• Increased absorption
POSSIBLE EFFECTS ON PHARMACOKINETIC PROFILE
• amine is ionised
HBD
X
Binding site
X= N or OCO2
-
Binding site
NH2R
Drug
+ NH
Drug
R2
+
AMINES
POSSIBLE BINDING INTERACTIONS
H-Bonding
Ionic Bonding
• Increased resistance to metabolism• Decreased excretion• Increased absorption
POSSIBLE EFFECTS ON PHARMACOKINETIC PROFILE
• Free base
AMINES
POSSIBLE BINDING INTERACTIONS
HBD
X
Binding site
X= N or O
X
Binding site
H
HBA
NH
Drug
RN
R
Drug
H
H-Bonding
1o amines
POSSIBLE ANALOGUES
2o aminesR2 NH
CH3COCl R2N
O
CH3
R NH2
CH3COCl
R
HN
O
CH3
R NHRCH3COCl
R
RN
O
CH3R NHR
CH3
VOC-Cl
O CH3
O
Demethylation
2o amine
3o amine with methyl substituent
2o amide
3o amide
3o amide
AMINES
CO2-
Binding site
No interaction
N CH3
O
R
Amide analogue
POSSIBLE EFFECT OF ANALOGUES ON BINDING
AMINES
• Increased resistance to metabolism• Increased excretion• Increased absorption
POSSIBLE EFFECTS ON PHARMACOKINETIC PROFILE
• Full synthesis of 1o-3o amines and amides
CO2-
Binding site
Ionic bonding
NR3
Drug
+
NR3
Drug
+
Induced dipole interactions
Binding site
δ +
δ -
POSSIBLE BINDING INTERACTIONS
POSSIBLE ANALOGUES
QUATERNARY AMMONIUM SALTS
Binding site (X= N or O)
XH
H-Bonding
HBA
ODrug
Binding site
ODrug
POSSIBLE BINDING INTERACTIONS
POSSIBLE ANALOGUES
R R'
O NaBH4 or LiAlH4
R R'
HO H
Ketone
Planar sp2 carbon centre
2o AlcoholTetrahedral sp3 carbon centre
Dipole-dipole interactions
ALDEHYDES AND KETONES
• If still active, further reactions can be carried out on alcohol to establish importance of oxygen
POSSIBLE EFFECT OF ANALOGUES ON BINDING
Change in stereochemistry
Binding site
XHH
OH
Alcoholanalogue
(X= N or O)
ALDEHYDES AND KETONES
• Increased susceptibility to metabolism• Increased excretion• Decreased absorption
POSSIBLE EFFECTS ON PHARMACOKINETIC PROFILE
POSSIBLE BINDING INTERACTIONS
X= N or OX
Binding site
H
OC
CH3
O
X
Binding site
H
O C CH3
O
ESTERS
POSSIBLE ANALOGUES
NaOH RC
OH
O
CH3HO+
Carboxylic Acid
Alcohol
LiAlH4 RCH2
OH
1o Alcohol
RC
O
O
CH3=
ESTERS
ESTERS
HydrolysisLoss of activity due to loss of other functional groups
only suitable for simple esters
• Increased resistance to metabolism• Increased excretion• Decreased absorption
POSSIBLE EFFECTS ON PHARMACOKINETIC PROFILE
POSSIBLE EFFECTS OF ANALOGUE ON BINDING
ESTERS
Reduction to alcoholcan establish importance of the carbonyl oxygen
reaction can be difficult to do if other labile functional groups are present
• Increased resistance to metabolism• Decreased excretion• Increased absorption
POSSIBLE EFFECTS ON PHARMACOKINETIC PROFILE
POSSIBLE EFFECTS OF ANALOGUE ON BINDING
C O
O
R CO
O
R C OH
O
Prodrug
esterase
Drug
ESTERS
Fattybarrie
r
OC
R
O
OC
R
O
OH
Prodrugesterase
Drug
Binding site (X= N or O)
X
H
Binding site (X= N or O)
X
HBA HBDN
Drug
H
O
R
N
Drug
H
O
R
H-bonding
AMIDES
POSSIBLE BINDING INTERACTIONS
RC
HN
OR'
LiAlH4
NaOH
NaH/ CH3I
RC
OH
OR'H2N+
Carboxylic acid
Amine
RCH2
NH2
1o Amine
RC
CH3N
OR'
3o
Amide
POSSIBLE ANALOGUES
AMIDES
POSSIBLE EFFECTS OF ANALOGUES IN BINDING
AMIDES
Hydrolysismay lead to a loss of activity due to loss of other functional groups
only suitable for simple amides
• Increased susceptibility to metabolism• Increased excretion• Decreased absorption
POSSIBLE EFFECTS ON PHARMACOKINETIC PROFILE
POSSIBLE EFFECTS OF ANALOGUES IN BINDING
AMIDES
Reduction to amineremoves carbonyl group can establish importance of the
carbonyl oxygenreaction can be difficult to do if
other labile functional groups are present
• Increased resistance to metabolism• Decreased excretion• Increased absorption
POSSIBLE EFFECTS ON PHARMACOKINETIC PROFILE
No binding as HBD
X
N
CH3
O
R
Analogue
binding site
Binding of O as HBA hindered
XH
N
CH3
R
O
steric shield
Analogue
POSSIBLE EFFECTS OF ANALOGUES ON BINDING
AMIDES
Binding site (X= N or O)
XHHBA
XH
HBAC
OH
DrugO
C
OH
DrugO
X
HC
O
DrugO
HBD
H-bonding
POSSIBLE BINDING INTERACTIONS
CARBOXYLIC ACIDS
as free acid
Binding site (X= N or O)
XHHBA
Binding site
NHR2
+
OC
O
Drug
- OC
O
Drug
-
H-bonding Ionic bonding
CARBOXYLIC ACIDS
as carboxylate ionPOSSIBLE BINDING INTERACTIONS
POSSIBLE ANALOGUES
RC
OH
OLiAlH4
H+ / R'OH RC
OR'
OEster
RCH2
OH 1o Alcohol
CARBOXYLIC ACIDS
No ionic bonding possible
NHR2
binding site
C
O
O
Analogue
CH3
+
H-Bonding hindered
XH
steric shield
C
O
O
Analogue
CH3
POSSIBLE EFFECT OF ANALOGUES ON BINDING
CARBOXYLIC ACIDS
binding site binding site
Drug
Drug
R R
hydrophobicregion
vdw
vdw
hydrophobicpocket
POSSIBLE BINDING INTERACTIONS
H2 / RaNiDrug Drug
H2 / Pd/CH
R'H
R H
R'H
RHH
POSSIBLE ANALOGUES
AROMATIC RINGS AND ALKENES
binding sitehydrophobicregion
binding site
hydrophobicpocket
Analogue
HH
Nofit
Analogue
R RHH
‘Buffers’
POSSIBLE EFFECT OF ANALOGUES ON BINDING
AROMATIC RINGS AND ALKENES
• Easiest alkyl groups to vary are substituents on heteroatoms
• Vary length and bulk of alkyl group to test space available
POSSIBLE ANALOGUES
Drug
Drug
Drug
Analogue
Analogue
Analogue
N CH3
VOC-ClN H
R'XN R'
HBr R'X
O
CH3O
H
O
R'
Hydrolysis R'OH
C
OCH3C
OH
O O H
C
OR'
O
ALKYL GROUPS
hydrophobic slot
binding site
Drug
CH3
van der Waalsinteractions
binding site
hydrophobic ‘pocket’
Drug
CH3CH3H3C
POSSIBLE BINDING INTERACTIONS
ALKYL GROUPS
MISCELLANEOUS FUNCTIONAL GROUPS IN DRUGS
Functional Group
Notes/Comments
Acid chlorides too reactive to be of use
Acid anhydrides too reactive to be of use
Alkyl halides present in anticancer drugs to form covalent bonds with nucleophiles in target
Aryl halides commonly presentnot usually involved in binding directly
Nitro groups sometimes present but often toxic
Alkynes sometimes presentnot usually important in binding interactions
Thiols present in some drugs as important binding group to transition metals (e.g. Zn in zinc metalloproteinases)
Nitriles present in some drugs but rarely involved in binding
PHARMACOPHORE
PHARMACOPHORE
IUPAC definition:
“..the ensemble of a steric and electronic features that is necessary to ensure the optimal supramolecular interaction with a specific biological target structure and to trigger (or block) its biological response.”
PHARMACOPHORE
Highest common denominator of a group of ligands exhibiting a similar biologic effect
Summarizes the important binding groups: required for activityRelative positions in space with respect to each
IMPORTANCE OF PHARMACOPHORE CONCEPT
PHARMACOPHORE-BASED LIGAND DESIGN
NH
CH3
CH3
OH OH
PHARMACOPHORE-BASED LIGAND DESIGN
Applied in 3 domains:
1. Definition of relevant pharmacophoric features in a drug molecule
necessary to achieve a certain biological effect and to establish clear SARs
2. Scaffold hopping detecting molecules with different scaffolds (novel
chemotypes) by virtually screening large compound libraries
3. Prediction of pharmacological profiles for lead structures in silico
to predict unwanted side effect in very early stages of the drug discovery process
to reduce the risk of late failure of drug candidates
PHARMACOPHORE MODELING
4 steps in development
1.selection of a set of active ligands known to bind to the same target (same binding site)
2.Conformational analysis for all ligands
3.assignment of pharmacophoric features
4.molecular superimposition of the ligand conformations to develop a common 3D pharmacophore
Problems with Pharmacophore-Based Modeling• Unavoidable emphasis on
functional groups as the crucial binding groups
• The strength of binding of the target to the drug cannot be taken into account
DRUG OPTIMIZATION STRATEGIES
IMPROVEMENT OF DRUG-TARGET INTERACTION
DRUG OPTIMIZATION STRATEGIES
IMPROVEMENT OF DRUG-TARGET INTERACTION
Homologous Series Vinylogues and Benzologues Isosteres and Bioisosteres Ring Transformations Conformational Restrictions Twin Drug Approach
HOMOLOGOUS SERIES
1. Monoalkylated Derivatives
2. Cyclopolymetheylenic Compounds
3. Open, Difunctional, Polymethylenic
4. Substituted Cationic Heads
HOMOLOGOUS SERIES
Chain Extension
Chain Contractio
n
Monoalkylated Derivatives
HOMOLOGOUS SERIES
Varying of length and bulk allows probing the depth and width of a hydrophobic pocket in the drug target
binding site
Drug
CH3CH3
H3C
binding site
hydrophobic ‘pocket’
Drug
CH3
HOMOLOGOUS SERIES
Larger alkyl groups often confer selectivity to target
Substituted Cationic Head
VINYLOGUES AND BENZOLOGUES
VINYLOGUES AND BENZOLOGUES
1. Vinylogue2. Ethynologue3. Benzologue
ISOSTERES AND BIOISOSTERES
Classical Isosteresatoms/functional groups with similar size, polarity, electronic distribution and bonding
NH
NH
O
O NH
NH
O
O
F
ISOSTERES AND BIOISOSTERES
Non-Classical Isosteresdoes not obey the steric and electronic rules used to define classical isosteres but have the same physical and chemical properties
S
NH NH2
N
NH NH2
N
NH NH2
N+
O-
O
N
NH NH2
SO
O
NH2
ISOSTERES AND BIOISOSTERES
Bioisosteresgroup that can be used to replace a functional group while retaining the desired biological activity
N
CH3
CH3CH3
OCH3
O
+ N
CH3
CH3CH3
ONH2
O
+
Towards receptor: BIOISOSTERE
Towards AcHE: NOT A BIOISOSTERE
RING TRANSFORMATIONS
Ring Opening
Ring Closure
RING TRANSFORMATIONS
Ring Expansion/ Contraction
NH
O O-
N
N
OO-O
N
N
O O-O
NH
OO-
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VARIATION OF RING SUBSTITUENTS• Steric hindrance• hydrophobic
properties• Electronic properties
OH
Y
Y
OH
RING TRANSFORMATIONS
RING TRANSFORMATIONS
“Benzo Cracking”
Restructuring of Ring System
RING TRANSFORMATIONS
CONJUNCTIVE APPROACH Addition of another
functional group to the lead compound
To probe extra binding interactions with the target
Effects: Frequently causes the
convertion of an agonist to an antagonist
Can cause increase in activity and selectivity of drug to its target
O
N
O
CH3
ONH
O-
O-
extension
O
N
O
CH3
ONH
O-
O-
RING TRANSFORMATION
CONJUNCTIVE APPROACH
RING TRANSFORMATIONS
DISJUNCTIVE APPROACH
N
HO
O
O
OHCH3
N
H
O
O
CH3
CH3
Cocaine
Procaine
Advantages
More flexible Can bind differently to targets May result to reduced activity May result to reduced
selectivity May lead to increased side
effects
Disadvantages
Easier, quicker, cheaper to synthesize
CONFORMATIONAL RESTRICTIONS
Incorporation of Rigid Functional Group
NH NH
NH2
N
N
O
O
O
OH
NH NH
NH2
N
N
O
O
O
OH
N
N
N
O
O
O
OHO
CH3
NH
NH2
Flexible chain
RigidRigid
CONFORMATIONAL RESTRICTIONS
DisadvantagesMore complicated to synthesize
No guarantee of retention of active conformation
A rigid molecule may no longer bind to the target if it changed its shape as a result of mutation
CONFORMATIONAL CONSTRICTIONS
O
NH
NS
O
O
F
F
F
Favors active conformation of
target
O
NH
NS
O
O
F
F
F
CH3H
Steric clash
O
NH
NS
O
O
F
F
F
CH3
H
Rejects active conformation of
target
TWIN DRUG APPROACH
Strategies
TWIN DRUG APPROACH
Strategies
TWIN DRUG APPROACH
Combination Mode
TWIN DRUG APPROACH
Symbiotic Approach
IMPROVEMENT OF PHARMACOKINETIC PROPERTIES
DRUG OPTIMIZATION STRATEGIES
IMPROVEMENT OF PHARMACOKINETIC PROPERTIES
Improving Absorption Manipulation of Metabolic
Susceptibility Selective Targeting Drug Alliances Prodrugs and Bioprecursors
IMPROVING ABSORPTION
Decrease PolarityVariation pKaBioisosteres Replacement
IMPROVEMENT OF ABSORPTION
Decreasing PolarityMasking of polar functional groupsAddition of alkyl group to the
carbon skeletonMethylene shuffle
CH3
N
NHN
N
O
CH3
CH3
S OO
N
N
CH3
methylene shuffle
CH3
N
NHN
N
O
CH3
S OO
N
N
N
CH3
CH3
N
NHN
N
O
S OO
N
N
CH3
N
CH3
IMPROVEMENT OF ABSORPTION
Variation of pKaPreferred pKa: 6-9Variation of N-alkyl substituents
Extra or larger - increases electron-donating effect but it also increases steric bulk
“wrapping up” N within a ring
Reduced basicity
Improved absorption
NH2 NH
O
NH
CH3
N
O
N
N
N NH2
O
NH
CH3
N
O
N
N
IMPROVEMENT OF ABSORPTION
Variation of pKaVariation of
Aromatic substituentsAddition of
electron-donating or electron-withdrawing substituents
Weak base Destabilized
CH3
CH3
NHCH3
N+O
-
O CH3
CH3
NH2+ CH3
N+O
-
O
H+
Cl
CH3
CH3
NHCH3
Cl
CH3
CH3
NH2+ CH3
H+
INCREASING ABSORPTION
Bioisosteres Replacement
O
O
Drug
H
NN
NN
Drug
H
• Ionized at pH 7.4• More lipophilic• Resistant to metabolic
reactions that degrade carboxylic acids
INCREASING RESISTANCE TO CHEMICAL AND ENZYMATIC DEGRADATION
Steric ShieldsUsually done to protect amides and esters
from hydrolysis
NO O
NH
SH
O
NH
CH3
CH3
NH
OCH3 CH3
CH3
O
NHCH3
INCREASING RESISTANCE TO CHEMICAL AND ENZYMATIC DEGRADATION
Electronic Effect of Bioisosteres Replacement of the metabophore without
affecting the pharmacophore
S
N
NH
OSH H
OOH
O CH3
OO
cephalothin
S
N
NH
OSO H
OOH
O NH2
OO
CH3
cefuroxime
INCREASING RESISTANCE TO CHEMICAL AND ENZYMATIC DEGRADATION
Stereoelectronic Modifications
O
O
NH2
NCH3
CH3
NHC
NH2 CH3
CH3
O
N
CH3
CH3
procaine lidocaine
INCREASING RESISTANCE TO CHEMICAL AND ENZYMATIC DEGRADATION
Metabolic Blockers
OO
CH3
CH3
OCH3
H
H
H
CH3
O
OO
CH3
CH3
OCH3
H
H
H
CH3
O
CH3
OO
CH3
CH3
OCH3
H
H
H
CH3
O
OH
Megestrol acetate
Metabolic oxidation
Metabolic oxidation
INCREASING RESISTANCE TO CHEMICAL AND ENZYMATIC DEGRADATION
Removal of Susceptible Groups
S
O
O
NHO
NH
CH3
CH3 S
O
O
NHO
NH
CH3
Cl
tolbutamide chlorpropramide
OH
OH
INCREASING RESISTANCE TO CHEMICAL AND ENZYMATIC DEGRADATION
Group Shift
OH
OH
NH2
OH H
Noradrenaline
Salbutamol
CH2
OH
OH
NH
CH3
CH3CH3
OH H
• May render the molecule unrecognizable to both the target and metabolic enzyme
OH
OH
NH
CH3
CH3CH3
OH H
OH
OH
COMT
O
OH
CH3
NH
CH3
CH3CH3
OH H
ACTIVE
INACTIVE
INCREASING RESISTANCE TO CHEMICAL AND ENZYMATIC DEGRADATION
Ring Variation
Cl
Cl
N
N
O
SCl
F
F
N
N
NN
N
N
OH
Tioconazole Fluconazole
DIMINISHING RESISTANCE TO DRUG METABOLISM
Introduction of Metabolically Susceptible Groups
N
N
SO
OCH3
Cl
N
N
SO
OCH3
Cl
CH3
O
OH
OH
DIMINISHING RESISTANCE TO DRUG METABOLISM
Self-Destruct DrugsHalf-life is controlledChemically stable under one set of condition but becomes unstable and spontaneously degrades under another set of conditions
Advantage:inactivation does not depend on the
activity of metabolic enzymes, which could vary from patient to patient
DIMINISHING RESISTANCE TO DRUG METABOLISM
N+
O
O
H
CH3R
H
NCH3
O
O
CH3
CH3
O
O
O
O
CH3
CH3
O
O
NCH3
O
O
CH3
O
CH3
O
CH3CH3
+ +
Atracurium
-H+
N
CH3
CH2O
O
H
R
+
SELECTIVE TARGETING
Targeting Tumor CellsTargeting Gastroinstestinal Tract Infections
Targeting Peripheral Regions rather than the Central Nervous System
SELECTIVE TARGETING
Mann ,J. 2002. Natural products in cancer chemotherapy: past, present and future Nature Reviews Cancer 2, 143-148 [online].Accessed [25 January 2009]
SELECTIVE TARGETING
Targeting Gastroinstestinal Tract Infections
ON
CH3NHS
O
O
NH2
ON
CH3N-
S
O
O
NH2
pKa = 6.0
SELECTIVE TARGETING
Targeting Peripheral Regions Rather than the Central Nervous System
N+
CH3
CH3
CH3
O
H
O
OH N
CH3
O
H
O
OHBr-
Ipatropium bromide atropine
CNS SIDE EFFECTS
DRUG ALLIANCES
Sentry DrugsLocalizing the Area of Activity of a Drug
Increasing Absorption
SENTRY DRUGS
Administration of a second drug alongside the principal drug
The second drug usually inhibits the enzyme that metabolizes the principal drugAmoxicillin + Clavulanic AcidLevodopa + Carbidopa
LOCALIZING THE AREA OF ACTIVITY OF A DRUG
Epinephrine + Procaine
Constricts blood vessels in the
vicinity of injection
Distribution throughout the
body is prevented
Prolonged anaesthetic activity
ADJUVANTS
increases gastric motilityIncreases absorption
O NHN
CH3
CH3
OCH3
Cl
NH2
Metoclopramide
PRODRUGS APPROACH
IMPROVING PHARMACOKINETIC PROFILE
PRODRUGS
More appropriatelydrug latentation
Intentional prodrug designThe chemical modification of a
biologically active compound to form a new compound, that upon in vivo enzymatic attack, will liberate the parent compound
2 main classes:BioprecursorsCarrier Prodrugs
CARRIER PRODRUGS
Criteria for Well-designed Carrier Prodrug:1.The linkage between the drug substance and the transport
moiety is usually a covalent bond.2.As a rule the prodrug is inactive or less active than the parent
compound. 3.The linkage between the parent compound and the transport
moiety must be broken in vivo.4.The prodrug, as well as the in vivo released transport moiety,
must be non-toxic.5.The generation of the active form must take place with rapid
kinetics to ensure effective drug levels at the site of action and to minimize either direct prodrug metabolism or gradual drug inactivation.
APPLICATIONS OF PRODRUG DESIGN
APPLICATIONS OF CARRIER PRODRUGS
Improvement of Membrane PermeabilityProlonging of Drug ActivityMasking of Toxicity and Side EffectsLowering Water SolubilityImprovement of Water SolubilityTargeting of DrugsIncreasing Chemical StabilityActivation by External Influence
IMPROVEMENT OF MEMBRANE PERMEABILITY
EstersN-methylationTrojan horse approach for carrier proteins
IMPROVEMENT OF MEMBRANE PERMEABILITY
EstersNot all are hydrolyzed efficientlyAddition of e-withdrawing groups
O
OR F
FF
O
OHR
+
O-
F
FF
O
OR CH3+
O
OHR CH3O-
IMPROVEMENT OF MEMBRANE PERMEABILITY
N-methylation
NHN
CH3
O
O O
CH3 NHNH
CH3
O
O Ometabolism
hexobarbitone
IMPROVEMENT OF MEMBRANE PERMEABILITY
Trojan horse approach
O
OH
NH2OH
OH
Amino acid
transporter
levodopa
Blood brain barrier
BLOOD
BRAIN
C OO
decarboxylase
NH2
OH
OH
dopamine
PROLONGING OF DRUG ACTIVITY
For sustained level of drug for long period of time
NH
S
F
FF
N
N
OO
CH3
Fatty ester
Fluphenazine decanoate
MASKING OF TOXICITY AND SIDE EFFECTS
OP
NH
O
N
Cl
Cl
OP
NH
O
N
Cl
Cl
OH
OP
NH2
O
N
Cl
Cl
O
OH P
NH2
O
N
Cl
ClCH2
H
O
cyclophosphamide 4-hydroxycyclophosphamide
aldophosphamidephosphoramide mustard
ACTIVE
REDUCING TOXICITY
Making drug resistant to metabolismAromatic nitro groupsAromatic aminesBromo arenesHydrazinesHydroxylaminesPolyhalogenated compounds
Variation of apparently harmless constituents
Variation of position of substituents
LOWERING WATER SOLUBILITY
R = - H
ChloramphenicolR = - CO(CH2)14CH3 Chloramphenicol palmitate
N+ O
-O
O
OHNH
O
Cl
Cl
R
IMPROVEMENT OF WATER SOLUBILITY
To enable infusion of a drug in higher concentration but smaller volume
R = - H
CHLORAMPHENICOL
R = - CO(CH2)2COOH
CHLORAMPHENICOL SUCCINATE
N+ O
-O
O
OHNH
O
Cl
Cl
R
TARGETING OF DRUGS
NN
N
NO
H H
NH4+++ H
+ + OH2
NN
N
N
INFECTED URINARY TRACT
BLOOD
STABLE AT pH > 5
Methenamine
INCREASING CHEMICAL STABILITY
N
S
OOH
CH3
CH3
NNH
O
CH3 CH3
O
N
S
OOH
CH3
CH3
NHNH2
O
O
O
CH3 CH3
+
Hetacillin
NH
S
OOH
CH3
CH3
NHNH2
O
OH
O
ampicillin
END OF LECTURE
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