Lecture 11 - Lipinski's Rule of Five in Drug Design and Rational Design of Pro-Drugs

Question 1

What is Lipiniski’s rule of five?

Answer 1

No more than 2 can be broken:
- < 5 HBD (OH + NH)
- ≤ 10 HBA (N + O)
- MW < 500
- clogP < 5
- compound classes that are substrates for biological transporter are exceptions

Question 2

Exceptions to the rule of five

Answer 2

Orally active compounds that break more than 2 rules include antibiotics, antifungals, vitamins, and cardiac glycosides

Question 3

What are pro-drugs?

Answer 3

Compounds which are inactive themselves but are converted by the body (i.e. metabolisation) to the active compound

Question 4

What problems do pro-drugs solve?

Answer 4

• Toxicity
• Bad taste
• Acid sensitivity
• Poor membrane permeability
• Short duration of action

Question 5

What are bioprecursor pro-drugs?

Answer 5

Compounds that already contain the embryo of the active species within the structure

Question 6

What are carrier pro-drugs?

Answer 6

Formed by combining an active drug with a carrier species to form a compound with the desired chemical and biological characteristics

Question 7

What are bipartate pro-drugs?

Answer 7

Carrier drugs that consist of the drug linked to the carrier species by a functional group

Question 8

What are the features of a carrier pro-drug? (5)

Answer 8

• less toxic than the parent drug
• the pro-drug should have minimal inherent activity
• the rate of formation of the drug from the pro-drug should be sufficient to maintain the concentration within the therapeutic window
• the metabolites (cleaved parts to form drug) have low toxicity
• pro-drug has improved bioavailability if given orally