Medicinal Chemistry

Is the science that deals with the design and development of pharmaceutical agents that has a desired biological effect on human body and other living systems.

Drug

• Is a compound that interact with a biological target to produce a biological response:

– Biological target: Human, bacteria, fungi,…– Biological response: desired or undesired.

• Sugar, salt, pesticides, herbicides, can be considered as drugs.

• Food and fizzy drinks also considered as drugs.

• Medicinal chemists concern about the synthesis of new molecules to investigate the relationships between the chemical structure of these compounds and their biological activities.

Medicinal chemistry also involves isolation of compounds from natural sources

The Ideal drug must be:

–Not toxic.–Effective and potent.–Selective.–Easily administered.–Cheap

In Reality, There is no Ideal drug.

• Penicillin: one of the safest and most active antibiotics……BUT….. Resistance developed to most of them.

• Morphine: a very effective pain killer….. BUT…. May cause tolerance, addiction and respiratory depression.

• Heroin: the best pain killer we know….BUT…. addiction developed (still used in terminal cancer).

• Drug might be harmful at higher doses:

– Therapeutic index: it is the ratio of the dose leads to toxic effect in 50% of cases to that leads to therapeutic effect in 50% of the cases.

Large therapeutic index…… safer drug.narrow therapeutic index…… more toxic

drug.

– Poisons can be drugs at lower doses:

Arsenicals: very toxic but used as antiprotozoal agents.

Tubocurarine: used as muscle relaxant.

Selective Toxicity

• Selective Drugs: that show toxicity against abnormal cells without affecting normal cells.

• Degrees of selectivity:

– No effect on normal host cells.– Killing certain microbial strain without affecting others.– Targeting certain metabolic pathway without affecting

others.

Drug Targets

• they are macromolecules (receptors, enzymes, DNA or transport proteins).

• Drugs interact and bind to the binding sites through intermolecular bonds (ionic, H-bonds, Van Der Waals, dipole-dipole and hydrophobic).

• The bonds mainly are weak, therefore in most of the cases this binding is reversible.

Human FAS

Orlistat

In medicinal chemistry:

• Pharmacokinetic: How the drug distribute and reach its target (ADME) and what will happen to the drug

• Pharmacodynamic: How the drug interact with its target.

• Pharmacokinetics – what the body does to the drug:

–How does drug get it into the body?–How long does it take to exert its

action?–How long does it stay in the body?–Where does it go to in the body?– Is it metabolised to another form?

The [plasma]-time curve after drug administration

Drug administered

Drug absorbed

availableDrug in the plasma

Drug at the site of action

Metabolic inactivation

ExcretionPool of non-available

Drug in the tissues

Which route?Which formulation?

Which barriers to cross?Gut, skin, lungs?Stability at the site of absorption?

•Plasma-protein binding?• Electrostatic charge•Tissue-protein binding?•Fat storage?

Passive diffusion?Active transport?Blood-brain barrier penetration?

Pharmacokinetics

Pharmacokinetic properties

ADME

Pharmacokinetic properties

• Drug administration: How is the drug to be formulated? If as an injection, is it soluble in aqueous solution? If as a tablet, will it dissolve when released in the gut?

• Drug absorption: can the drug pass through the

barrier membranes in the GIT? Can it pass through the skin barriers? These barriers are made up in a large part by lipids, so the drug must be sufficiently lipophilic/ unionized to diffuse through them.

• Membranes have phospholipids bilayer that act as barriers to the movement of drugs within the body

Pharmacokinetic properties

• Drug metabolism: metabolism increases the water solubility of drugs by enzymatically introducing polar functional groups so that they can be excreted: what is the chemistry of the drug? How fast is it inactivated? Is it converted into more active or even toxic components?

• Drug excretion: the kidney excretes water-soluble metabolites and the ionized forms of drugs.

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• Pharmacodynamics – what the drug does to the body:

–What is the therapeutic effect of the drug?–How does it exert its effect?–How does the drug interact with the target?–Can the effect be modified?

• More than 90% of drugs have biological targets to bind with in order to exert their pharmacological effects.

– Biological targets: are endogenous macromolecules including DNA, RNA, enzymes, receptors, membrane proteins, etc…

DNA

Protein

The nature of drug-receptor binding

• Either reversible or irreversible.• Reversible binding means that the drug-target

complex will dissociate to release the free functioning target.

• Irreversible binding means permanently blocking the binding site of the target… irreversible damage.

Interactions involved in drug-receptor interaction

• Includes:Covalent bonding Irreversible bond

Ionic (electrostatic) interaction

Reversible bonds

Dipole-dipole interaction

H-bonding

Hydrophobic interaction

Van der Waals forces

O NHOH

HN

O

XH

Practolol inside the adrenergic B-receptor

Hydrophobic interactionIonic bonding

Hydrogen bonding

Aromatic interaction

Dipole-dipoleinteraction

OH

O

O

N

O

HyoscineAnti-cholinergic

N

Cl

Cl

HO

O

Chlorambucil (Leukeran)for chronic leukemia

PtNH2

OOH2N

O

O

Oxaliplatin

Pharmacokinetics and Pharmacodynamics: are they

inter-related?

The answer is definitely yes

• If for a reason or another the drug will not reach the target, no pharmacological effect will be observed even if the drug is known to effectively bind to the target active site.

• If the drug has a proper pharmacokinetic properties and deposited in enough concentration around the site of action, it must effectively bind to the target to exert its biological effects

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What do we mean by:

Oral availability Oral stability

Tissue availability Oral activity

Oral availability Oral stability

Tissue availability Oral activity

What do we mean by:

• Oral availability or bioavailability measures the fraction of the drug being absorbed into the blood circulation.

• Factors affecting oral availability:– Chemical nature of drug (lipophilicity and ionization

state).– Water solubility.– Oral stability.– Physiological factors.

Oral availability

• Oral stable drugs must be:– Chemically stable toward the GIT conditions; acidic

stomach and basic intestine.– Enzymatically stable (first-pass metabolism): stable

toward the digestive and metabolizing enzymes such as esterase, amidase and oxidase enzymes.

• If the drug is orally unstable it will not be available to be absorbed…..low oral availability.

Oral stability

• First pass metabolism does not mean only liver metabolism of orally administered drugs before the drug being deposited in blood.

• It covers all metabolic transformation happened to the drug after oral administration before reaching the systemic circulation.

Oral stability

• First pass metabolism includes:

– All Oral cavity enzymes such as amylase and lingual lipase– Stomach pepsinogen– All GIT proteolytic enzymes.– All Intestinal hydrolase enzymes such as esterase,

amidase and carbohydases.– All intestinal lipases and reductase enzymes.

Oral stability

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Oral availability Oral stability

Tissue availability Oral activity

Oral availability Oral stability

Tissue availability Oral activity

• Orally active agents are drugs either active locally in the GIT lumen (such as in the case of gastroenteritis) or must be absorbed into the blood circulation.

• Factors affecting oral activity:– Chemical and enzymatic stability of drugs.– The physiological nature of the GIT lumen.– The same factors affecting the oral availability in the case

of systemically active agents.

Orally activity

• Systemically active agents must be stable in the GIT as well as during the first pass metabolism if reaching the liver before the blood circulation.

• The locally acting agents must be just stable in the GIT, it does not necessarily absorbed through intestinal membrane, they will just act locally:– Given in active form.– Given as prodrug…activated in GIT by special enzymatic

reactions

Orally activity

• Example:– Paromomycin is one of the aminoglycosides that is

widely used in GIT infections caused by salmonella, Shigella and Amoeba.

– It is active after oral administration although it has a very limited oral absorption (highly polar compound).– It will only work locally.

Orally activity

http://en.wikipedia.org/wiki/File:Paromomycin_structure.svg

• Example:– Sulfasalazine; a commonly used drug in ulcerative

colitis, although it will be given orally, small quantity will be absorbed.

– It will be reduced by colorectal azoreductase to give the active sulfapyridine and P-aminosalicylic acid…both are active

Orally activity

N

SNH

O O NN

HO

HO

O

H2N

SNH

O O N

Azo reductase

NH2

HO

HO

O

5-amino salicylic acidSulfapyridine

• Tissue availability means the amount of the drug that reached the site of action or the target tissue.

• In most cases, tissue availability is lower than the oral availability due to one of the following factors:– Extensive drug metabolism.– Blood protein binding.– Rapid drug excretion.– Fat deposition of drug.– Many barriers to penetrate to reach the site of action.

Tissue Availability

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The molecular properties of drugs

• It is the physicochemical properties of drugs.

• These properties fundamentally affect every thing the drug does to the body (the pharmacodynamic aspects) and what the body does to drugs (the pharmacokinetic aspects).

• the molecular properties also determine which dosage form and the route of administration is suitable for the given drug.

Molecular properties of interests

1. Partition coefficient.2. Dissociation constant (degree of ionization).3. Solubility (aqueous and fat solubility).4. Chemical stability.5. Biological stability (metabolic profile of

drugs).

Drug solubility

• Is drug soluble enough in the GIT content?

• Is it soluble enough in blood to be given parenterally?

• More water soluble drug in blood….large volume of distribution.

• More water soluble drugs…poor penetration into CNS through the lipophilic blood brain barrier.

• More water soluble drugs…poor penetration into CNS through the lipophilic blood brain barrier.

• As a result, very limited number of drugs can act on CNS.

Pores

•Partition coefficient•Lipophilicity/hydrophilicity

•Ionisation/dissociation constant•Strong or weak acids/bases•Salt formation

•Solubility•Water-soluble salts•Lipid soluble esters

•Stability•Chemical degradation – oxidation, hydrolysis, light•Enzyme degradation (metabolism) esterases, amidases, cytochrome P450

Physicochemical properties of drugs

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Lipophilicity/hydrophilicity of drugs

CH3

OH

OH

OH

O

H

H

Donor

Donor

Acceptor

Acceptor

Partition coefficient• Is the measurement of the drug water solubility.• Partitioning means that the drug will be divided in parts between the

water and the oil layer.

– P = [Co ]/[Cw]– LogP = Log[Co ]/[Cw].

• LogP > 2 lipophilic drug.• LogP < 2 hydrophilic drug• LogP only applied to neutral compound• Low logP….. Low penetration to CNS• High logP….. Low water solubility…. Not suitable for oral

administration

Partition coefficient and drug ionization

• Once the drug become ionized, its partitioning will definitely be changed since it will be more polar, water soluble than the neutral form.

• This is very important to keep in mind when administering drugs that will be ionized in GIT, because this will affect their absorption.

For an acid substance For a base substance

• Papp is the apparent partition coefficient, which varies with pH, • For acids, at pH values below the pKa, Papp = P, since ionization is

suppressed and the drug is only in unionized . • At pH values above the pKa the value of Papp decreases because the

species is ionizing and moving into the aqueous layer.

pKapHappPP

101

PARTITIONING OF ACIDS AND BASE

pHpKaappPP

101

Consider drugs that are acids, for example RCOOH, which has a pKa of 4.0, and a Partition coefficient of 200.

• Papp becomes 198 in the stomach suggesting that absorption will take place

• pH 8.0 in the small intestine, the calculated Papp suggests no absorption.

BiologicalMembraneGut Contents

RCOOH

RCOO+H

RCOOH Drug Absorption

X No Drug Absorption

An example about the relation between the Papp and P :

In stomach

In intestine

• Ionized drug will have lower lipophilicity than the neutral form.

– is the degree of dissociation in water, depends on the ionization constant.

• LogD: is the log of distribution coefficient that describe the lipophilicity of ionizable compound

Example of logD

LogD pH-1.31 2.00.12 7.51.73 10.0

ONH

OH

OMetaprolol

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Ioni

zatio

n in

crea

ses

By lo

wer

ing

the

pH

Basic group with a Pka of 10