In drug development, bioavailability of
a drug in the target tissue is a necessary precondition of the
therapeutic benefit. Beyond this, however, it's necessary to
consider how the drug can actually get from the bottle – to the
desired point of action.
Due to the greater number of patients
taking one or more drugs for chronic conditions, it is increasingly
imperative to design drugs that can be administered orally. Oral
administration is a practical and highly economic mode of therapy,
that simplifies the delivery of medical care and improves patient
compliance with the intended dosing regimen.
In a drug development program,
drug-like properties are designed in at the lead-optimization
stage, by synthesis of many analogs, careful observation of their
properties, and application of medicina chemistry principles.
Lipinski's Rules... How to make a compound that has good oral bioavailability
In a study of thousands of drug
compounds, Chris Lipinski, then at Pfizer, observed a regularity in
“Drug-Like Properties” of the many compounds that were
successfully administered orally – had good oral bioavailability. In addition to being water soluble,
such drugs had properties and attributes that became known as
“Lipinski's Rule of Five”, or more commonly, Lipinski's Rules:
Ideal Properties of an Orally available Drug
Molecular weight -- less than 500 daltons
Octanol/Water partition coefficient,
logP – less than 5
No more than 5 Hydrogen-bond donors
No more than 10 Hydrogen-bond acceptors
Rotatable bonds -- less than 1
Ref: C. A. Lipinski, “Drug-Like Properties
and The Causes of Poor Solubility and Poor Permeability”, J.
Pharmacol. Toxicol. Methods, 44, 235 (2000)
As a generalization good water
solubility is favored by low molecular weight; low logP; more H-Bond
donors and acceptors; and greater charge and/or polarity. Membrane
absorption is favored by higher logP; less H-bonding; less charge and
polarity, and more flexibility. All of these same factors also have
a bearing on metabolism and elimination, as well.
Achieving a drug with favorable oral
bioavailability involves a trade off of physicochemical properties in
the proposed drug molecule. Hence the general guidelines given above
provide guidance as to what has worked in the past in the majority of
The most recent review of these factors
concludes that lipophilicity; percent polar surface area; and H-Bond
donor count are the most important. Average values have not changed
significantly between populations of pre-1983 and post –1983 drug
compounds. In contrast, mean values of molecular weight, N+O count;
H-Bond acceptor count; rotatable bonds and rings have increased 13 to
29% in the post 1983 drug group.
Properties of marketed oral drugs:
Average of Oral Drugs
( N+O ) 3.74
Polar Surface Area
Ref: P. D.
Leeson and A. M. Davis, “Time-Related Differences in the Physical
Property Profiles of Oral Drugs”, J.
Med Chem., 47, 6338