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

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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 instances.

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:

Compound Property	Average of Oral Drugs 1983-2002
Molecular Weight	377
cLogP	2.5
HB Donors	1.77
HB Acceptors	( N+O ) 3.74
Rotatable Bonds	6.42
Polar Surface Area	102.2
Rings	2.88

Ref:  P. D. Leeson and A. M. Davis, “Time-Related Differences in the Physical Property Profiles of Oral Drugs”, J. Med Chem., 47, 6338 (2004)