ND - Drug Development II

Question 1

Why do we need to modify a lead target drug? (5)

Answer 1

1. Generate new specificities
2. Increase target selectivity
3. Increase bioactivity
4. Increase efficacy and potency
5. Change ADME profiles: membrane permeability, elimination, toxicity profile

Question 2

What are 4 general characteristics of small molecular weight drug like molecules?

Answer 2

1. Simple diffusion: depends largely on lipid solubility or the partition coefficient and the molecular size. Most orally available drugs.

2. Facilitated diffusion: aquaporins, glucose transporters

3. Active transport: ABC transporters (often important in pumping drugs out) , SLC family

4. Endocytosis

Question 3

What is the importance of compartment pH in adsorbtion and elimination of drugs?

Answer 3

Intravenous use of morphine (and derivatives) can easily be detected in the stomach as a consequence of its pKa and ion trapping.

Question 4

Where do acidic drugs and basic drugs accumulate?

Answer 4

Acidic drugs accumulate on basic side

Basic drugs accumulate on the acid side

Question 5

What is the Lipinsky rule of 5 for orally available drugs?

Answer 5

• molecular weight < 500
• octanol-water partition coefficient logP < 5
• < 5 H-bond donors (sum of NH and OH)
• < 10 H-bond acceptors (sum of N and O)

Question 6

What subtle changes can be maid to change the characteristics of drugs? (3)

Answer 6

• New receptor interaction to increase potency and modulate bulk properties
• Find a substitution position not affecting potency where bulk properties can be modulated for good DMPK
• Trade potency for DMPK improvements dose to man focus

Question 7

What are isosteres?

Answer 7

Isosteres are those atoms or groups of atoms or molecules or compounds (organic or inorganic) that have the same arrangement and/or number of electrons (isoelectronic) or similar shape (isosteric).

• These isosteres share many similar chemical properties

Question 8

What are bioisesteres?

Answer 8

Molecules which possess broadly similar biological activities and identified by identical physical or chemical properties

Question 9

What is an example of bioisosteres?

Answer 9

Uracil and 5-FU:

• 5-FU: anticancer drug that covalently binds to thymidylate synthetase to inhibit DNA replication.

Guanine and 6-Thioguanine

• Thioguanine utilised by hypoxanthine-guanine phosphoribosyltransferase. Inhibits DNA replication

Question 10

How does Salbutamol work to relieve asthma or COPD symptoms?

Answer 10

By binding to beta-2 receptors in the airways, causing relaxation of smooth muscle cells and bronchodilation (opening of the airways)