Physical Properties 3 Lecture

Question 1

Define intermolecular H bonds

Answer 1

Virtually non-existent between small molecules in water

- Both donor and acceptor must first break H bonds to surrounding water molecules

Question 2

Define intramolecular H bonds

Answer 2

Readily formed in water
Entropically more favorable
- More disorder in the water molecule surroundings

Question 3

H bonding and bioavailability

Answer 3

Oral drugs are absorbed through the gut walls
De-solvation and formation of a neutral molecule is unfavorable if the compound forms many H or ionic bonds with water
With too may HBA or HBD, drug won’t get into the gut

Question 4

Define molecular size

Answer 4

One of the most important factors affecting biological activity and the most difficult to measure

Question 5

What are the ways of determining molecular size?

Answer 5

Molecular weight
Electron density
Polar surface area
Van der Waals surface
Molar refractivity

Question 6

Define polar surface area

Answer 6

Measure of what proportion of the surface of the molecule is comprised of polar groups, compared to the proportion of hydrophobic groups
More substantial influence on CNS drugs

Question 7

Define rotatable bonds

Answer 7

Defined as any single non-ring bond, attached to a non-terminal, non-hydrogen atom

Question 8

If you have a compound with a lot of rotatable bonds?

Answer 8

Super floppy
Opens itself up to attack by a whole bunch of enzymes
Less rigid- might prevent from getting chopped up by enzymes (longer action, longer lasting)

Question 9

What drugs exhibit good-to-excellent oral bioavailability?

Answer 9

Fairly rigid compounds (seven or fewer rotatable bonds

More than 10 bioavailability = poor bioavailability)

Question 10

When a drug is looking at entering clinical trails you must look at?

Answer 10

Solubility
Hygroscopicity (absorbs water from the air and degrades itself)
Crystalline forms
Chemical stability

Question 11

What is Lipinski’s Rule of Five for oral drugs?

Answer 11

Molecular weight less than 500
LogP less than 5
Less than 5 H bond donors (sum of NHs and OHs)
Less than 10 H bond acceptors (sum of Ns and Os)

Question 12

What is Veber’s rule?

Answer 12

Less than 10 rotatable bonds

Question 13

What is the drug design conundrum?

Answer 13

While pharmacokinetic properties improve by modulating bulk properties, potency also depends on these

Question 14

Three ways to approach potency?

Answer 14

New receptor interaction to increase potency
Find a sub position not affecting potency
Trade potency for DMPK improvements

Question 15

Issues with new receptor interactions?

Answer 15

This is an addition of H bonds which increases or decreases logD