Molecular properties that influence the oral bioavailability of drug candidates.

Oral bioavailability measurements in rats for over 1100 drug candidates studied at SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline) have allowed us to analyze the relative importance of molecular properties considered to influence that drug property. Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of molecular weight. That on average both the number of rotatable bonds and polar surface area or hydrogen bond count tend to increase with molecular weight may in part explain the success of the molecular weight parameter in predicting oral bioavailability.

Internal mobility of cyclic RGD hexapeptides studied by 13C NMR relaxation and the model-free approach.

The internal mobility of three isomeric cyclic RGD hexapeptides designed to contain two beta-turns in defined positions, cyclo(Arg-Gly-Asp-Gly-D-Pro-Pro) (I), cyclo(Arg-Gly-Asp-D-Pro-Gly-Pro) (II) and cyclo(Arg-Gly-Asp-D-Pro-Pro-Gly) (III), have been studied by 13C NMR longitudinal and transverse relaxation experiments and measurements of steady-state heteronuclear (1H)-13C NOE enhancement with 13C at natural abundance. The data were interpreted according to the model-free formalism of Lipari and Szabo, which is usually applied to data from macromolecules or larger sized peptides with overall rotational correlation times exceeding 1 ns, to yield information about internal motions on the 10-100 ps time scale. The applicability of the model-free analysis with acceptable uncertainties to these small peptides, with overall rotational correlation times slightly below 0.

The soluble form of E-selectin is an asymmetric monomer. Expression, purification, and characterization of the recombinant protein.

The gene coding for a soluble form of human E-selectin (sE-selectin) has been expressed in Chinese hamster ovary (CHO) cells. Cells seeded into a hollow fiber reactor secreted protein at a level of 160 mg/liter. The protein was purified to > 95% pure and low endotoxin (< 2 ng/mg), using physiological pH and buffers.

Conformations of cyclic pentapeptide endothelin receptor antagonists.

The solution conformations in methanol and chloroform of the endothelin A receptor antagonists cyclo(dV-L-dW-dD-P), 1, and cyclo(dV-N alpha-MeL-dW-dD-P), 2, have been studied by NMR spectroscopy at room temperature and below. In these solvents, both peptides were found to have a well defined peptide backbone conformation composed of a type II beta turn at the Leu-D-Trp and a gamma' turn at Pro. This conformation is in agreement with results reported for 1 in other solvents and consistent with the expected location of the N-methyl substituent in that backbone.