Factors that influence oral bioavailability; A cathepsin K inhibitor for human studies
The development of drug candidates that demonstrate favorable pharmacokinetic properties has been a major issue limiting the use of peptides as leads in the drug discovery process. Conventional wisdom has placed peptides as intractable leads both because of the presence of the peptide bond and the high molecular weight that is common to any compound that exceeds the tripeptide level. The analysis by Lipinski of the properties common to human drugs  that led to his “rule of 5” generally finds peptides as deficient in these properties. A more recent analysis of a more structurally diverse database of the rat oral bioavailability of drug candidates from our laboratory at SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline or GSK) added new insight to the definition of properties that should be considered for achieving good oral bioavailability . In addition to representing examples from nearly all programs at SmithKline Beecham over more than 10 years of research,...
KeywordsOral Bioavailability Rotatable Bond Polar Surface Area Methyl Substitution Rotational Freedom
I am thankful for the continuing valued discussions on these topics with Dr. Kenneth D. Kopple.