HAMMETT AND HANSCH PLOT

IN DRUG FORMULATION

Presented by Naraino Majie Nabiilah

and Joorawon Svenia

Date: 10th November 2014

Table of Content

• Introduction

• Modification of lead compound

• Drug design

– a) Lipophilicity

–b) Electronic effects (Hammett plot)

– c) Steric effects

–d) Hansch analysis

• Morphine as example

• Conclusion

• References

Hammett

Louis Plack Hammett (April 1894- February 1987)was an American physical chemist. He is knownfor the Hammett equation which relates thereaction rates and equilibrium constant for someclasses of organic reactions including substitutedaromatic compounds. He was awarded for hisnumerous discoveries in 1961, 1967 and 1975.

Hansch

Corwin Herman Hansch (October 1918- May2011) was a Professor of Chemistry in USA andbecame known for his concept of QSAR, thequantitative correlation of the physicochemicalproperties of molecules with their biologicalactivities. He is known as the father of computer-assisted molecule design.

INTRODUCTION

INTRODUCTION

• SAR is an advance designed to find the relationshipsbetween chemical structure and biological activity ofstudied compounds.

• Therefore it is the concept of linking chemical structure toa chemical property or biological activity includingtoxicity.

• The theory of SARs is to produce new drugs with similarstructure and effects as the original one but with havingmore potency and improved side-effects.

• Moreover, SARs are essential for toxicological studies on acompound.

• SARs have been used since long ago to design chemicalswith the commercially wanted properties and thus they areimportant while designing drugs as the chemicals withdesired pharmacological and therapeutic activities areknown.

• There are various factors that should be considered

while developing the mechanism of SARs, these are:

– the size and shape of the carbon skeleton,

– the nature and degree of substitution and

– the stereochemistry.

• During modifications on a drug analogue, effects on

water solubility, transport through membranes, receptor

binding, metabolism and other pharmacokinetics

properties should be considered.

• Computer assisted molecular modelling helps to solve

this problem by providing accurate targeting.

INTRODUCTION

MODIFICATION

OF LEAD

• Varying size and shape

– Changing the number of methylene groups in chains and

rings

• This increases lipophilicity which results in an increased in activity

• Water solubility is reduced as well as activity

• No selective binding due to micelle formation in aliphatic

compounds

– Increasing or decreasing the degree of unsaturation

• A change in the degree of unsaturation causes an increase in

rigidity, complication of E-Z isomers, more sensitivity and

increased toxicity.

– Introducing or removing a ring system

• This results to an increase in size, shape changes and stability of

structure with the substitution of C=C double bonds.

MODIFICATION OF LEAD

• Introduction of new substituents

–New substituents may occupy the same position as

the previous compound but each will have its own

characteristics, pharmacokinetic and

pharmacodynamics properties to the analogue.

• Methyl group

• Halogen group

• Hydroxy group

• Amino group

• Carboxylic group

• Sulphonic group

MODIFICATION OF LEAD

• Bioisosterism

–Substituents or groups with chemical and physical

properties.

–Can attenuate toxicity, modify activity of a lead and

–Alter the pharmacokinetics profile of the lead.

–There are two types of bioisosterism:

• Classical isosteres- have same number of atoms and fit

the steric and electronic rules and have similar biological

activity

• Non- Classical isosteres- do not have same number of

atoms and do not fit the steric and electronic rules but

have similar biological activity

MODIFICATION OF LEAD

DRUG DESIGN

• SAR general equation is:

Biological activity = function {parameter(s)}

The following should be considered for drug design

a) Lipophilicity

Partition coefficient (P) and lipophilicity substituent constant

(π) are the two parameters that represent lipophilicity.

DRUG DESIGN

i) Partition coefficients (P)

P is used to measure the movement of drug through membranes. Theaccuracy of the correlation of drug activity with P depends on the solventsystem used. The equation below shows the relationship between P and drugactivity:

log (1/C) = k1 log P + k2

k1 and k2 are constants and the equation indicates a linear relationshipbetween the activity of the drug and its partition coefficient.

ii) Lipophilic substituent constants (π)

The lipophilic substituent constant (π) can be calculated todetermine the contribution that different substituents make tothe hydrophobicity of the compound.

π = log PRH – logPRX

PRH : Partition coefficient of the unsubstituted molecule

PRX : Partition coefficient of the molecule carrying substituentX

+ π value indicates accumulation of compound in organic layer (Higher lipophilicity of the substituent)

- π value indicates accumulation of compound in aqueous layer (Higherhydrophilicity of the substituent)

DRUG DESIGN

b) Electronic effects

• The activity of a drug is also affected by the distribution of

electrons in the molecule.

• Drugs in unionised form are carried easier through the

membranes compared to drugs in ionised form.

• The Hammett constant is used to quantify the electronic effects.

i) Hammett constant (σ)

σX = log (KBX/KB)

The distribution of electrons in a molecule depends on the natureof the electron withdrawing or donating group present in thatdrug. The Hammett constant calculates the equilibrium and rateof chemical reactions.

DRUG DESIGN

c) Steric effects

(i) Taft steric parameter (Es)

Show the relationship between shape and size of a drug, the dimensionsof its target site and the drug’s activity

(ii) Molar refractivity (MR)

A measure of both the volume of a compound and how easily it ispolarized.

(iii) Other parameters

Van der Waals’ radii

Charton’s steric constants

Verloop steric parameters

DRUG DESIGN

d) Hansch analysis

• It tries to relate drug activity to measurable chemical

properties. According to Hansch, drug action is divided into 2

stages:

– Transport of drug to its site of action

– Binding of drug to target site

• Each stage depends on chemical and physical properties of

drug and target site.

• Hansch suggested that biological activity of drug is related to

parameters by the mathematical equation:

DRUG DESIGN

• The accuracy of the above equation depends on:

–The number of analogues (n) used; greater n

more accurate

–The accuracy of biological data used in the

derivation of equation

–Choice of parameter

• Accuracy also depends on values of standard deviation

and regression constant.

• Hansch analysis is used to indicate the importance of a

parameter on a mechanism by which a drug acts.

DRUG DESIGN

CRAIG PLOTS

• Helps in determining suitable susbtituents to

quickly decide which analogs to synthesize.

• Plots of one parameter against another.

–For example, p vs. s

• Once the Hansch equation has been derived, it

will show whether p or s should be negative or

positive in order to get good biological

activity.

MORPHINE

MORPHINE

• Morphine, C17H19NO3, is the most abundant of opium’s 24

alkaloids, accounting for 9 to 14% of opium-extract by mass.

• Named after the Roman god of dreams, Morpheus, who also

became the god of slumber, the drug morphine numbs pain,

alters mood and induces sleep.

• Less popular and less mentioned effects include nausea,

vomiting and decreased gastrointestinal motility.

• The three dimensional structure of morphine is fascinating.

• It consists of five rings, three of which are approximately in

the same plane.

• The other two rings, including the nitrogen one, are each at

right angles to the other trio.

1923

MORPHINE

Structure

MORPHINE

1923

Structure

MORPHINE

1923

Structure

Structure

Structure

Structure

Structure

T-Shaped molecule

Structure

Log P: 0.89

Potential Binding Groups

Functional groups

Carbon skeleton

Phenol

Ether

Alcohol

Amine

O

NMe

HO

HO

Potential Binding Groups

Phenol

Ether

Alcohol

Aromatic

ring

Alkene

Amine

O

NMe

HO

HO

Potential Binding Groups

Structure Activity Relationships

• Mask or remove a functional group

• Test the analogue for activity

• Determines the importance or other wise of a

functional group for activity

STRUCTURE ACTIVITY

RELATIONSHIPS

O

NMe

HO

HO

O

NMe

HO

STRUCTURE ACTIVITY

RELATIONSHIPS

O

NMe

HO

HO

STRUCTURE ACTIVITY

RELATIONSHIPS

O

NMe

HOSTRUCTURE ACTIVITY

RELATIONSHIPS

O

NMe

HO

HO

STRUCTURE ACTIVITY

RELATIONSHIPS

SAR - The phenol moiety

R=H Morphine

R=Me Codeine

Codeine 20% active (injected peripherally)

0.1% active (injected into brain)

NMe

O

RO

HO

HH

Log P: 1.19

SAR - The phenol moiety

Notes

Codeine is metabolised in the liver to morphine.

The activity observed is due to morphine.

Codeine is used for mild pain and coughs

Weaker analgesic but weaker side effects.

Conclusion

Masking phenol is bad for activity

SAR - The phenol moiety

R=Ac 3-Acetylmorphine

Decreased activity

•Acetyl masks the polar phenol group

•Compound crosses the blood brain barrier more easily

•Acetyl group is hydrolysed in the brain to form morphine

NMe

O

RO

HO

HH

SAR - The 6-alcohol

R=Me Heterocodeine

5 x activity

NMe

O

HO

RO

HH

SAR - The 6-alcohol

•Activity increases due to reduced polarity

•Compounds cross the blood brain barrier more easily

•6-OH is not important for binding

NMe

O

HO

HO

NMe

O

HO

O

NMe

O

HO

Log P: 2.50Log P: 0.89

Morphine Hydromorphone

Log P: 0.90

Desomorphine

SAR - The 6-alcohol

R=Ac 6-Acetylmorphine

Increased activity (4x)

•Acetyl masks a polar alcohol group making it easier to cross BBB

•Phenol group is free and molecule can bind immediately

•Dependence is very high

•6-Acetylmorphine is banned in many countries

NMe

O

HO

RO

HH

Log P: 1.55

SAR - The 6-alcohol and phenol

R=Ac Heroin

Increased activity (2x)

•Increased lipid solubility

•Heroin crosses the blood brain barrier more quickly

•Acetyl groups are hydrolysed in the brain to generate morphine

•Fast onset and intense euphoric effects

NMe

O

RO

RO

HH

Log P: 1.58

SAR - Double bond at 7,8

Dihydromorphine

Increased activity

The alkene group is not important to binding

NMe

O

HO

HO

HH

Log P: 1.26

SAR - Nitrogen

No activity

Nitrogen is essential to binding

CHMe

O

HO

HO

HH

SAR - Methyl group on nitrogen

NR= NH Normorphine

Reduced activity (25%)

•Normorphine is more polar and crosses the BBB slowly

•Ionized molecules cannot cross the BBB and are inactive

•Ionized structures are active if injected directly into brain

•R affects whether the analogue is an agonist or an antagonist

No activity

NR= N+Me2

No activity

NR

O

HO

HO

HH

O

NR= NMe+

-

Log P: -1.56

N-Oxide

Quaternary

salt

SAR - Stereochemistry

Mirror image of morphineNo activity

10% activity

Changing the stereochemistry is detrimental to activity

NR

O

HO

HO

HHNR

O

HO

HO

HH

HBD or HBA

Ionic

(N is protonated)

van der Waals

SAR - Important binding interactions

NMe

O

HO

HO

HH

CONCLUSION

CONCLUSION

• Medicinal chemistry has and will continue to play an important

role in today's society as it deals with development, synthesis

and design of pharmaceutical drugs.

• These results are then used to give us a better understanding of

diseases as well as giving us ways of preventing and curing

them.

• Although medicinal chemistry is about creating new drugs, the

properties and quantitative structure activity relationships

(QSAR) of existing drugs is important to see if a combination

of these biological properties can be mixed with a new hit to

produce the latest drug that will help fight against various

diseases.

CONCLUSION

• As the majority of medicinal chemistry is based around the

discovery of new drugs and development many companies

spend a considerable amount of money and maintaining and

improving their database of information to ensure that each

test is run as efficient as possible.

• Of course, thousands of compounds related to the morphine

structure have been prepared and many without activity, and

no compound has been found to halt the terrible addictive

morphine properties.

• Used correctly, the morphine family is an important class of

analgesics, and their study represents an important

contribution to the understanding of medicinal activity.

REFERENCES• ANON, 2014. Assessment of chemicals. Introduction to (Quantitative)

structure activity relationships [online]. Available from: http://www.oecd.org/chemicalsafety/risk-assessment/introductiontoquantitativestructureactivityrelationships.htm

• MCKINNEY, J.D. et al, 2000. Toxicological sciences. The practice of structure activity relationships (SAR) in toxicology [online], 56(1), 8-17. Available from: http://toxsci.oxfordjournals.org/content/56/1/8.full

• PARIKH, 2009. Medicinal Chemistry. The SAR & QSAR approaches to drug design [online]. Available from: http://faculty.mville.edu/parikhs/courses/chm2004/lecture%20notes/CHM%202004%20Lectures%20-%20Chapter%204.pdf

• TOROK, B. Medicinal chemistry. SAR and QSAR [online]. Available from: http://alpha.chem.umb.edu/chemistry/ch458/files/Lecture_Slides/Lecture_Chapter_3.pdf [Accessed on 8 November 2014].

• MANIBUSAN, M. et al, 2012. Technical working group on pesticides. (Quantitative) structure activity relationship [(Q)SAR] guidance document [online]. Available from: http://www.epa.gov/oppfead1/international/naftatwg/guidance/qsar-guidance.pdf

REFERENCES

• ANON, 2014. Wikipedia. Louis Plack Hammett [online]. Available from: http://en.wikipedia.org/wiki/Louis_Plack_Hammett

• ANON, 2014. Wikipedia. Corwin Hansch [online]. Available from: http://en.wikipedia.org/wiki/Corwin_Hansch

• Medicinal Chemistry- Chapter 3, QSAR of Morphine. Available at: http://carbon.indstate.edu/rfitch/CHEM%20452/Chapter_3.pdf

• Anon, Morphine Chemistry, Online. Available at: http://www.emsb.qc.ca/laurenhill/science/morphine.html

• Anon, 2012, A Look at the Morphinan Structure Activity Relationships of Six Popular Opiates, Online. Available at: http://opiophilia.blogspot.com/2012/12/opiate-structure-activity-relationship.html

• Florencio Zaragoza Dörwald : Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds