Medichem
Seminar
Chap4. Lipinski Rules
Park, Sook Jin
School of Pharmacy, Sungkyunkwan University
2015. 9. 30. Fri. seminar.
4.1 Lipinski Rules
“Rule of 5”
by Lipinski (Pfizer)
- Classifying the key physicochemical properties of drug-like
compounds.
< Point of making “5 rules” >
1. Easy & Fast, No cost to use.
2. Easy to remember.
3. Intuitively evident to medicinal chemists.
4. Widely used standard benchmark.
5. Based on solid research, documentation and rationale.
6. Work effectively.
Medichem Seminar
Lipinski Rules
POINT1
> 5 H-bond donors
(expressed as the sum of all OHs and NHs)
POINT2
> 10 H-bond acceptors
(expresed as the sum of all Ns and Os)
POINT3
MW > 500
POINT4
Log P > 5
POINT5
Substrates for biological transporters are exceptions
to the rules
Medichem Seminar
Lipinski Rules
R-OH
R-COOH
R-NH2
R-NH-R’
R-CO-R’
R-COO-R’
R-O-R’
R-C≡N
Medichem Seminar
Lipinski Rules
MW(molecular weight) is related to the size of the
molecule.
Molecular size ↑, a lager cavity must be formed in
water in order to solubilize the compound.
And then, Solubility↓, Absorption↓
POINT3
MW > 500
POINT4
Log P > 5
POINT5
Substrates for biological transporters are exceptions
to the rules
Medichem Seminar
Lipinski Rules
POINT1
> 5 H-bond donors
(expressed as the sum of all OHs and NHs)
POINT2
> 10 H-bond acceptors
(expresed as the sum of all Ns and Os)
Increasing logP also decreases aqueous solubility,
which reduces absorption.
logP↑, Solubility↓, Absorption↓
POINT4
Log P > 5
POINT5
Substrates for biological transporters are exceptions
to the rules
Medichem Seminar
Lipinski Rules
POINT1
> 5 H-bond donors
(expressed as the sum of all OHs and NHs)
POINT2
> 10 H-bond acceptors
(expresed as the sum of all Ns and Os)
Membrane transporters can either enhance or reduce
compound absorption by either active uptake transport or
efflux, respectively.
Thus, transporters can have a strong impact on increasing
or decreasing absorption.
POINT5
Substrates for biological transporters are exceptions
to the rules
Medichem Seminar
Application of Rules for Compound Assessment
H-bond donor < 5
H-bond acceptor < 10
MW < 500
logP ≤ 5
≤ 12 total hydrogen
bonds
Figure 4.1 Doxorubicin
Lipinski Rules
 H-bond donors =
7
 H-bond acceptors = 12
 MW = 543
 ClogP = -1.7
Application of Rules for Compound Assessment
2000-fold increase in potency
H-bond donor < 5
H-bond acceptor < 10
MW < 500
logP ≤ 5
≤ 12 total hydrogen bonds
Medichem
Seminar