EVALUATION OF PHYSICOCHEMICAL PARAMETERS IMPORTANT TO THE ORAL BIOAVAILABILITY OF PEPTIDE-LIKE COMPOUNDS - IMPLICATIONS FOR THE SYNTHESIS OF RENIN INHIBITORS
Hw. Hamilton et al., EVALUATION OF PHYSICOCHEMICAL PARAMETERS IMPORTANT TO THE ORAL BIOAVAILABILITY OF PEPTIDE-LIKE COMPOUNDS - IMPLICATIONS FOR THE SYNTHESIS OF RENIN INHIBITORS, Journal of medicinal chemistry, 38(9), 1995, pp. 1446-1455
A series of radiolabeled compounds related to renin inhibitor structur
es was synthesized to represent a range of physicochemical properties.
These compounds were tested in assays for intestinal absorption and h
epatic clearance in order to define parameters conducive to optimizing
bioavailability. In general, compounds with higher Lipophilicity were
better absorbed from the intestine. Absorption may also be dependent
on molecular charge, as compounds with ionizable functionality were le
ss well-absorbed than neutral compounds. Neutral compounds showed some
dependency on molecular weight, with smaller compounds exhibiting bet
ter absorption. While uptake into hepatic cells was rapid regardless o
f partition coefficient or molecular weight, rate of appearance in bil
e was dependent on the molecular weight of the compounds.