Lipinsky rules for CNS drugs:

Question 1

What is the normal Lipinsky rule of 5?

Answer 1

1. No more than 5 Hydrogen bond donors
2. No more than 10 Hydrogen bond acceptors (mainly N and O)
3. Molecular weight under 500
4. LogP under 5

Question 2

What are the Lipinski rules for CNS drugs?

Answer 2

Two or fewer H-bond donors
Six or fewer H-bond acceptors
Molecular weight below 400
LogP still below 5
Potent activity
Not a CYP3A4 inducer and not a high affinity for P-gp substrate (standard for all drugs)
Not an acid: Acid at physiological pH will be 100% ionised so will not cross the BBB
Must be neutral or basic with a pKa of 7.5 to 10.5

Question 3

How would you overcome the fact that a CNS drug is a Carboxylic acid?

Answer 3

Create an ESTER pro-drug that can cross the BBB, and then be hydrolysed to form the active Carboxylic Acid.

Question 4

What formulation is normally with a LogP of below 0?

Answer 4

Injection

Question 5

What formulation is normally with a LogP of medium 0-3

Answer 5

Oral

Question 6

What formulation is normally with a LogP of high 3-4?

Answer 6

Transdermal

Question 7

What formulation is normally with a LogP of very high 4-7?

Answer 7

Toxic build up in fatty tissues so not used.

Question 8

Drugs should be designed with what possible LogP?

Answer 8

The lowest possible to reduce toxicity, reduce non-specific binding, and ease formulation and bioavailibility.

Question 9

Drugs should be designed with what possible MW?

Answer 9

Lowest possible but in a balance: Not too low so that they are more likely to bind to other receptors, but low enough to lower the risk of allergic reactions.