Physicochemical Properties In Relation To Biological Activity

Physicochemical Properties in Relation to Biological Activity Yan Zhang, Ph.D. Department of Medicinal Chemistry [email protected]

A. Drug Distribution and Pharmacological Response

Drug in formulation

Drug in solution

Deggregation, dissolution

Drug in blood

absorption across membrane 2

1. Absorption

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pH values in each part of our GI tract: Stomach: 1-3 Small Intestine: ~7 large Intestine: 7-8

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1

2. Protein Binding

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3. Membrane Structure

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Phospholipid Molecule „

The unique chemical structure of phospholipid molecule decides the character of the membrane architecture.

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2

Passive Diffusion

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Active Transport

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4. Distribution and Excretion „

After the absorption, some drug molecules will act on target site, some may be metabolized. Eventually all the drug molecules would be excreted from our body.

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3

ADME

„ „ „ „ „

Absorption Distribution Metabolism Excretion (Toxicity)

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B. Properties that Influence Passage of Drugs Across Membranes 1.Partition Coefficients [Drug]octanol P=

[Drug]water

The higher the P value is, the better hydrophobic property the drug may have, the easier they are going to be absorbed. Log P is usually used. Only unionized (non-charged) compounds are lipid soluble while ionized drugs normally do not cross membrane as easy. 11

2. Acid/Base Partition „

Henderson-Hassalbach equation

[ base form ] pH = pKa + log [acid form ] The pH value of the solution in which drug is dissolved.

A constant for any given molecule

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Example In the stomach 2.5=4.5+logB/A -2=logB/A 1/100=B/A „ How about in the small intestine? 7.5=4.5+logB/A 3=logB/A 1000/1=B/A Conclusion: in the stomach, ibuprofen will mainly be in the acid form, which is less polar compared with its base form (charged mode), therefore, it is easier to be absorbed. On the other hand, in the small intestine, it is the opposite. „

COOH Ibuprofen pKa = 4.5

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Example 2 In the stomach 2.2=9.2+logB/A -7=logB/A NH2 1/10,000,000=B/A Amphetamine „ In the small intestine 7.2=9.2+logB/A -2=logB/A pKa = 9.2 1/100=B/A Conclusion: in the stomach, amphetamine will be mainly in its acid form, which is charged. Since it is very polar in the charged form, it will be very difficult to be absorbed. Similarly, in the small intestine, the dominated form is still the acid one, which makes it still not easily absorbed. „

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C. Properties and Biological Activity 1. Bonding Forces Bond type Covalent Reinforced ionic

Bond strength (kcal/mol) 40-140 10

Example CH3-OH H R N H O C R1

H

Ionic Hydrogen

5 1-7

O

R4N+ R

IR1

O H

O

C R2

Ion-dipole

1-7

Dipole-dipole

1-7

Van der Waals

0.5-1

hydrophobic

1

R4N+ ---- :NR3 O

C

NR3

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Example S1

S2 O

HC

S3

H

Me

N

CH C

C O

O 2 Zn

H

N

O O2C H

O

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Lock and Key Concept Drugs

Receptor types

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3D binding model

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2. Isosterism and Bioisoterism Comparison of Physical Properties of N2O and CO2 Property

N2O

CO2

148 X 10-6

148 X 10-6

Density of liquid at 10 ºC

0.856

0.858

Refractive index of liquid, D line 16 ºC

1.193

1.190

Dielectric constant at 0 ºC

1.593

1.582

Solubility in alcohol at 15 ºC

3.250

3.130

Viscosity at 20ºC

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Isosterism: replacement or modification of functional groups with other groups having similar perperties Grimm’s Hydride Displacement “Law”

C

N

O

F

Ne

CH

NH

OH

FH

CH2

NH2

OH2

CH3

NH3 20

Burger: Bioisosteres are compounds or groups that posses near equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties such as hydrophobicity. Bioisosteric compounds affect the same biochemically associated system as agonist or antagonists and thereby produce biological properties that are related to each other. 21

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Classical Bioisosteres (groups within the row can replace each other) Monovalent

Divalent

F, H OH, NH F, OH, NH, or CH3 for H SH, OH Cl, Br, CF3

-C=S, -C=O, -C=NH, -C=C-

Ring equivalents

S

N

O

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Examples for Bioisosteres O

O H

HN O

O

N H Uracil

R

N

F

HN N H

H2NO2S

S

NH O

R=Cl, Br, CF3

5-F-uracil

While uracil is an anti-cancer agent, substitution of one proton with fluorine atom lead to another antineoplastic agent 5-F-uracil.

O

For the thiazide diuretics, different substitutions do not change the electronic and hydrophobic properties of the molecule very much while the size of the substitutions are significantly different.

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3. Geometric Isomeric Aspects of Biological Activity: C C A

B

A

B

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Another example OH

OH

HO

OH

HO HO trans Diethylstilbestrol

Estradiol

„

cis

The inter-atomic distances between the OH groups in trans-diethylstilbestrol and in estradiol are similar, accounting for the greater estrogenic activity of the trans isomer.

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4. Conformational Aspects of Biological Activity:

„ NMe3

NMe3 H H

H

H O

H H3COC H

COCH3

anti or staggered

H

O H

While anti or staggered conformation is more stable (lowest energy), eclipsed one is not favorable for biological activity of acetylcholine.

eclipsed

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5. Optical Isomerism and Biological Activity: Stereochemistry & Chirality „

Stereochemistry deals with the arrangement of atoms and groups in three dimensions.

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Stereoisomers are possible when there is a chirality in the molecule.

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Chirality is due to asymmetry

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Chiral center, chiral axis and chiral plane

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Optically active 27

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Enantiomers

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Chirality is the necessary and sufficient condition for the existence of enantiomers.

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Enantiomers are nonsuperimposable mirror images of one another.

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Share common structural characteristics, as well as most of the same physical and chemical properties.

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Show Optical activity 28

Today we realize that most naturally occurring medicinal agents exist in their optically active or single isomer form, such as Quinine, Ephedrine and Pseudoephedrine Almost half number of the drugs in use are chiral. Normally only one enantiomer having the beneficial effect. In the case of some drugs, the other enantiomer can even be harmful

„

„ „ „

OH O H

H H2N O H

OH

H3C

O

Left-handed Ibuprofen powerful pain killer

O

O H

O

H

OH

N

H2N O

H

HO

OH H

N

OH H

CH3 O

Right handed Ibuprofen No activity

Right handed Aspartame not at all sweet slightly bitter

Left-Handed Aspartame “Nutrasweet” 160 times sweeter than sugar 29

Importance of Chirality „

Pharmacological Affinity to receptor: The binding specificity of a chiral receptor site for a chiral molecule is usually only favourable in one way Potency: In enantiomeric drugs, potency differences may arise because the more active enantiomer has a greater capability of achieving a pharmacophoric conformation 30

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Pharmacokinetics Absorption: Methotrexate, the L-enantiomer of the drug are actively absorbed while the D- form absorbed in the intestine by passive diffusion Distribution: The S enantiomer of propranolol is selectively bound in heart, whilst the R isomer is selectively incorporated into the adipose tissue. Metabolism: R enantiomer of warfarin has longer elimination half life. S-warfarin is metabolized by CYP 2C9, R-warfarin is metabolized by CYP 1A2, 2C19 and 3A4 Excretion: Renal clearance of plasma Quinidine is four times greater than quinine, its diastereoisomer

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Toxicological effect Antagonistic effect Teratogenicity Mutagenicity/Carcinogenicity O

H N

H N

O

O

O

H O

O H O

N

N

(S)-thalidomide (effective drug)

O

(R)-thalidomide (dangerous compound)

The body racemises each enantiomer, so even pure S is dangerous as it converts to R in the body.

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