Drug Selection

What are factors to consider when selecting a molecule for further development?

1. Receptor activity and selectivity

2. Biological issues

• Routes of administration

• Metabolism issues

3. Physics-chemical issues

• Ionisation potential (pKa)

• Solubility (logP)

• Biopharmaceutics Classification System (BSC)

• Lipinski’s Rule of 5

• Formulatability

4. Chemical issues

• Synthesis

• Stability

5. Patentability

Receptor Activity and Selectivity

Things to consider

Why are these things important to consider?

• What is the target receptor?

• What is the:

  • E_max (maximumum efficacy of the drug)

  • EC₅₀ (conc at which 50% of E_max is reached)

  • IC₅₀ (conc at which there is 50% inhibition)

• Effect on other receptors:

  • Side effects

  • ‘Dirty drugs’ e.g. haloperidol which affect many different receptors

Allows us to:

• Achieve the target biological effect

• Calculate the dose correctly

• Predict side effects

• Predict possible interactions and contra-indications

Explain what a receptor agonist and antagonist are

Receptor agonist: stimulates a receptor to promote the normal biological activity resulting from binding of the endogenous ligand.

Receptor antagonist: It binds to the receptor, but does not activate it. It "blocks" the action of the endogenous ligand or other agonists

Why is important to understand how a drug works in the body

• Target biological effect can be achieved

• Correct dose can be calculated

• Potential side-effects can be predicted

• Potential drug interactions and contra-indications can be predicted

You need to select a compound for development as a new anti-hypertensive, you have been given some data from your basic discovery colleagues, as shown.

1. Which one of the receptor activities will give the anti-hypertensive effect?

2. What side-effects are likely to be experienced by the patient?

3. What factors do you need to consider when evaluating these drugs? Explain your answer.

4. Which drug would you take forward for further development (if any)? Explain your answer.

α1 antagonist: causes vasodilation (not very specific - several side effects)

β2 antagonist: causes vasoconstriction

β1 antagonist: cardioselective, decreases heart rate and workload (more specific than α1)

2. α1 antagonist: α1 receptor stimulation causes smooth muscle vasoconstriction » inhibition causes reduction in bp

   β2 antagonist: β2 receptor stimulation causes smooth muscle relaxation e.g. bronchodilation » inhibition causes bronchoconstriction

   β1 antagonist: β1 receptor stimulation increases cardiac output, heart rate and blood pressure » inhibition causes reduction in bp

Potency on the target receptor: The most potent is Compound C (lowest IC50) and the least potent is Compound B (highest IC50)

Ratio between β1 and β2 activity: A greater separation means that off-target effects would be reduced at the clinical anti-hypertensive dose. Compound B is the best (ratio 1:25). Compound C is the worse (ratio 1:2)

Ratio between β1 and α1 activity: A greater separation means that off-target effects would be reduced at the clinical anti-hypertensive dose. Compound C is the best (ratio 1:25,000). This is 1:250 for A & B.

1. Describe the five modes of absorption of drugs across the intestine mucosa. What are the properties of the drugs that are processed in each route?

2. What are the factors mitigating against oral drug absorption? How do they work? What are the problems with this?

3. You have a range of compounds that you are studying. With respect to the effect of the mitigating factors discussed in Question 4, what would happen to the blood levels of your new compound in the following scenarios?

(A) Passive diffusion. Small non-ionized drug, in aqueous solution.

(B) Active transport. Drug needs to resemble natural molecules.

(C) Paracellular transport. Small and highly hydrophilic drug.

(D) Micellar delivery. Lipophilic drug.

(E) Via the immune system. Drug targeting the immune system

What are the factors mitigating against oral drug absorption? How do they work? What are the problems with this?

After an oral drug enters the gut lumen, it must cross intestinal epithelial cells to reach the blood. Two major systems reduce how much drug gets into the circulation:

1. P-glycoprotein (P-gp)

• A membrane efflux pump in intestinal epithelial cells

• Pumps drug molecules back into the gut lumen

• Reduces net absorption

2. CYP3A4

• A drug-metabolising enzyme in enterocytes

• Metabolises drugs before they reach systemic circulation

• Causes first-pass metabolism

Together, they act as a double barrier: even if a drug enters the cell, it may be metabolised (CYP3A4) or pumped out (P-gp).

How can CYP3A4 and P-gp explain drug-drug and drug-food interactions

Both CYP3A4 and P-gp can be induced or inhibited by other drugs or foods:

• Induction → more enzyme/pump → less absorption

• Inhibition → less enzyme/pump → greater absorption

Common drug and food interactions

• Rifampicin » induces CYP3A4

• Phenytoin » induces PGP

• Ketoconazole » inhibits both PGP and CYP3A4

• Grapefruit juice » inhibits CYP3A4

In each scenario, what would happen to the blood levels of your new compound in the following scenario:

a) Your patient is stabilised on your new orally-delivered compound, Compound D (metabolised by CYP 3A4). The patient is then given oral rifampicin as well as Compound D.

b) Your patient is stabilised on your new orally-delivered compound, Compound E(processed by PGP). The patient is then given oral phenytoin as well as Compound E.

c) Your patient is stabilised on your new orally-delivered compound, Compound F (processed by PGP and metabolised by CYP 3A4). The patient is then given oral ketoconazole as well as Compound F.

d) Your patient is stabilised on your new orally-delivered compound, Compound G (not processed by PGP and not metabolised by CYP 3A4). The patient then makes a change to his diet (to try to be more healthy) and starts to take his medicine at breakfast with grapefruit juice.

a)

• ↑ CYP3A4 activity

• ↑ intestinal metabolism

• ↓ drug reaching blood

Net effect: Lower absorption in blood

b)

• ↑ efflux back into gut lumen

• ↓ net uptake

Net effect: Lower absorption in blood

c)

• ↓ metabolism

• ↓ efflux

• More drug crosses into bloodstream

Net effect: Greater absorption in blood

d)

• ↓ first-pass metabolism in gut

• ↑ systemic exposure

Net effect: Increased absorption / higher blood levels

Explain the important of logP of a drug in its oral absorption

logP

• The ratio of the concentrations of a (non-ionised) solute between two solvents

• If one of the solvents is water and the other is a non-polar solvent, log P becomes a measure of hydrophobicity (or lipophilicity)

logP < 0 (more hydrophilic)

logP > 0 (more hydrophobic)

logP = 0 (same affinity for both phases)

Explain the important of pKa of a drug in its oral absorption

Provides information on how much drug is in the ionised or un-ionised state, at various pH conditions

pKa

Acid Dissociation Constant

pKa

Base Dissociation Constant

How much is in the ionised and unionised state in the stomach (pH = 1.0) and terminal ileum (pH = 7.0) for the following drug:

Acidic drug with pKa = 3.0

How much is in the ionised and unionised state in the stomach (pH = 1.0) and terminal ileum (pH = 7.0) for the following drug:

Acidic drug with pKa = 6.0

How much is in the ionised and unionised state in the stomach (pH = 1.0) and terminal ileum (pH = 7.0) for the following drug:

Basic drug with pKa - 9.0

How much is in the ionised and unionised state in the stomach (pH = 1.0) and terminal ileum (pH = 7.0) for the following drug:

Basic drug with pKa = 12.0

What is the Biopharmaceutics Classifications System (BCS)

Classifies all drugs into 1 of 4 classes

state all the classes in BCS

Class 1: High solubility, high permeability

Class 2: Low solubility, high permeability

Class 3: High solubility, low permeability

Class 4: Low solubility, low permeability

What BCS class is the most favourable?

Class 1: High solubility, High permeability

Has the highest bioavailability

What does high solubility refer to?

Highest dose is soluble in 250mL or less of aqueous medium with a pH of 1-6.8

What does high permeability refer to?

No less than 85% of the administered dose is expected to be absorbed

Application of BCS

Developing formulations of a drug

• If drug is class 1

  • Dissolves rapidly and rapidly absorbed across the gut

  • So good bioavailability

  • So any formulation can be used

• If drug is class 2

  • Dissolution rate is likely to limit absorption

  • So use formulations that enhance dissolution rate

• If drug is class 3

  • Dissolves rapidly but poorly permeable

  • So formulation used needs to release drug rapidly to maximise the time the drugs have to permeate the GI tract

• If drug is class 4

  • Very poor bioavailability

  • Oral route might be impossible so we need to consider a prodrug

What is a prodrug?

inactive or less active form of a drug that is metabolized in the body to produce its active form

What is the BCS-based biowaiver?

• Approves generic drugs

• By doing bioequivalence studies using the BCS

• A way to compare 2 drugs without human studies

What is bioequivalence?

• When the two drug products (generic vs branded) release the same amount of active ingredient into the bloodstream at the same rate and extent when given at the same molar dose

• This ensures that a generic drug works the same way as the original branded drug

Which class of drugs may be able to be licensed without the need for a BCS-based waiver?

• Class 1

• Class 3

For the following compounds, estimate their BCS classes based on the information given

Explain Lipinki’s ‘Rule of 5’ and why it is important in compound selection

• A rule to determine if a pharmaceutical compound has chemical and physical properties that would make it an orally active drug

• It can be used during drug discovery to optimise activity and selectivity of a pharmaceutical compound

Rule of 5:

Molecular weight ≤ 500 - greater solubility, enhances diffusion

Log P ≤ 5 - greater absorption

H-bond donors ≤ 5 - greater membrane partition and permeability

H-bond acceptors ≤ 10 - greater membrane partition and permeability

For the following drug, state whether it complies with the Rule of 5:

Diazepam

For the following drug, state whether it complies with the Rule of 5:

Aspirin

For the following drug, state whether it complies with the Rule of 5:

Benzylpenicillin

For the following drug, state whether it complies with the Rule of 5:

Testosterone

Given the following information on their chemical synthesis, which compound would you choose to take forward as a development candidate. Explain your answer

1. Compare number of steps

• Compound M has the lowest number of steps

2. Calculate overall yield for each compound (yield ^{number of steps}):

Compound L: Overall yield = 0.75⁵ = 0.24 = 24%

Compound M: Overall yield = 0.7⁴ = 0.24 = 24%

Compound N: Overall yield = 0.9⁶ = 0.53 = 53%

3. High temperatures?

• Compound M and N dont use high temperatures

4. Cost

• Compound L has the lowest cost, Compound M has medium cost

Compound N is the best development candidate:

• Highest overall yield by far → less starting material, less waste

• No high-temperature steps → safer, easier to scale

• Medium cost per step, offset by much better yield

• Despite having more steps, the high per-step efficiency dominates

How long is a patent term?

How long is the development time?

• 20 years from first registration

• About 10 tears