Professional Documents
Culture Documents
• Target Validation
– Gene knockout, RNAi
• Drug Lead Identification
– Natural products, natural product analogs, natural product inspired
synthetic agents, synthetic drugs (rational design), synthetic drugs (HTS),
serendipity
• Develop SAR (Structure-Activity-Relationships)
– Structural features of a drug important to its biological activity
2
Physicochemical properties of a drug
Receptors for
Gastrointestinal track / desired effects
subcutaneous injection
Systemic circulation
Drug/
Drug Metabolites Metabolites
Drug/drug metabolites
Criteria for an Ideal or Close-to-Ideal Drug
• Must be soluble in, and transported by bodily fluids
– Aqueous phase
http://www.ucer.info/colitis_ph_level.html
Ionizable Drugs in World Drug Index
7
Manallack, D. T. Perspect. Medicin. Chem. 2007, 1, 25–38.
Changing the Polarity/Solubility of a Drug
• Medicinal chemists modify chemical structures of a drug to
change the polarity and pKa – addition of substructures
• Salt formation also affect solubility
– Phosphate, sulfate, citrate – increases water solubility
H H O
N NH 2
N F F
H OH 2.6
-0.4 O HH
R
H N 5 O F O
H
N OH OH
3.2
F N NH 2 4.2 3.3
8
H
Acid/Base Property of Drugs
10
Functional Groups that are Acidic
OH O
phenol 9-11 R R
O O
sulfonamide 9-10 R S NH2 R S NH
O O
imide 9-10 O O O O
R N R' R N R'
H
N-aryl- 6-7 O
H
R S N R S N
O
sulfonamide O
R'
O
R'
O O O O O O
sulfonimide 5-6 R
S
N R' R
S
N R'
H
O O
Alkylcarboxylic 5-6 R C OH R C O
Acid O O
OH O
R R
Arylcarboxylic 4-5
acid O O
O O
sulfonic acid 0-1 R S
OH
R S
O
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Principles of Medicinal Chemistry, 7th Ed., Foye, Lemke, Williams, Roche and Zito, Eds., William & Wilkins, 2012.
Functional Groups that are Basic
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Principles of Medicinal Chemistry, 7th Ed., Foye, Lemke, Williams, Roche and Zito, Eds., William & Wilkins, 2012.
Sample Exercise: Functional Groups
O O
O O Cl Me
S O
H 3C NH N
O NH S
OH Clopidogrel
Tirofiban
(Plavix)
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Sample Exercise: Acidic/Basic Functional Groups at
Physiological pH
O O O
OH O O O S
O NH N N
S N H
N N
Me N H H O H 2N
H
O Me
Me N
O O Me
H 2N Me N
CH3 N
O O
O N CH3 O N N
O H Me
OH 14
Acid/Base Chemistry
Example: O
OH
O 16
Aspirin
Henderson-Hasselbach Equation
17
Principles of Medicinal Chemistry, 7th Ed., Foye, Lemke, Williams, Roche and Zito, Eds., William & Wilkins, 2012.
Percent Ionization Formula
19
Ionization of a Drug
HO Me HO Me
N N H
+H
O O
-H
H H
HO HO
Morphine
pKa = 7.87
O Me H O
Me N S
N Me
N O
O N Me
O N N O O
Me H O
O H 3C O
20
Calculating %I
OH OH
+H
NH 2 NH 3
-H
CH3 CH3
Using eq.2:
(pH-pKa)
% ionization = 100/1+10
(7.4-9.4) (-2)
% ionization = 100 / (1 + 10 ) = 100/(1+10 )
= 100/(1+0.01) = 100/1.01 = 99% 21
Calculating %I
HO Me HO Me
N N H
+H
O O
-H
H H
HO HO
Morphine
pKa = 7.87
22
Calculating %I
OH O
Me Me
O O O
O
CH3 CH3
N -H
N
O +H O
Cl Cl
Indomethacin
pKa = 4.5
23
Summary
24
Lipophilicity
For Example:
P = [drug](octanol) / [drug](aqueous)
Drug(aqueous) Drug(octanol)
[AH](oct) + [A-](oct)
D=
[AH](aqu).+ [A-](aqu)
28
Water Solubility of Drugs
29
Polar Functional Groups and H-Bonds
H H H
O H
O
H
H O
H
O H H
N
H O
O R R'
H
H
H R' R'
R N R N R N
H H R"
3 2 1
Besides oxygen, and nitrogen, what is another atom that is capable of 30
H-bonding?
Water Solubility of Salts of Drugs
31
Water Solubility Prediction – I
Lemke’s method
Water solubilizing potential of organic functional groups when present in a
mono- or polyfunctional molecule (Table 2.5 in the textbook)
_________________________________________________________
Functional Monofunctional Polyfunctional
Group Molecule Molecule
_________________________________________________________
Alcohol 5 to 6 carbons 3 to 4 carbons
Phenol 6 to 7 carbons 3 to 4 carbons
Ether 4 to 5 carbons 2 carbons
Aldehyde 4 to 5 carbons 2 carbons
Ketone 5 to 6 carbons 2 carbons
Amine 6 to 7 carbons 3 carbons
Carboxylic acid 5 to 6 carbons 3 carbons
Ester 6 carbons 3 carbons
Amide 6 carbons 2 to 3 carbons
Urea, Carbamate 2 carbons 32
Lemke’s Approach
OH
H
HO
34
Examples
O OH HO Me
O N
OH
Me N O
O H
H
H 3C O
HO
35
Water Solubility Prediction – II
Table 2.6 – Hydrophilic-lipophilic Values (πV) for Organic Elements
An analytical approach Functional Group π value (aliphatic) π value (aromatic)
developed by Cates based H 0.00
upon approximate Alkane 0.50 0.56 (Me); 1.02 (Et)
calculation of logP for a Alkene 0.82
molecule - logP of a drug C6H5 (phenyl) 2.15
greater than 0.5 means Br, Cl, F, I 0.60; 0.39; -0.17, 1.0 0.86; 0.71; 0.14; 1.1
poorly water soluble; logP of IMHB 0.65
a drug ≤ 0.5 means freely NH2 (primary amine) -1.19 -1.23
water soluble. NHR (secondary amine) -0.67 0.47
NHR2 (tertiary amine) -0.30 0.18
LogP = Σπ ( hydrophobic -NHC=OR (amide) -0.97
substituent constants) Sulfur 0.0
OH -1.12 -0.67
OCH3 -0.02
38
Examples
HO O
HN NH 2
O H
O
OH N S
Me O O O
H N
Me Me O Cl
O OH
Me
HO
OH
39
Limitations to drug distribution – site of loss
Most drug molecules do not survive to reach the site of action. They
can undergo:
• Protein binding
• Binding to neutral fats
• Drug metabolism
• Excretion
40
Limitations to Drug Distribution – Site of Loss
• Protein Binding
– Drugs bind to albumin in a reversible fashion
– Binding is due to ionic and/or nonionic bonding, and is nonselective
– Lipophilicity/acidic features on the drug generally tend to increase
protein binding
– Bound drug cannot cross the membranes – ineffective
– Bound drug cannot be metabolized or excreted, therefore protein binding
can prolong the duration of drug’s activity
• e.g. typanocides, suramin
• Clinical Significance
– Bound drug/endogenous ligands can be displaced by other drugs leading
to drug interactions
• e.g. anticoagulant warfarin is displaced from its albumin-binding sites by several
drugs such as phenylbutazone, clofibrate, sulfonamides, etc.
• e.g. protein bound bilirubin can be displaced by the sulfonamides and other organic
anions 41
Limitations to Drug Distribution – Site of Loss
• Neutral Fats
– Make up to 20-50% of the body weight
42
Next Class
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