ABSTRACT
A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the specificity studies of the matrix metalloproteinases and the similar biological activity of aggrecanase and MMP-8. Incorporation of the side chain of a tyrosine residue into compound 1 as the P1' group provided modest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2') to conformationally constrain 2. Further optimization resulted in compound 11, a potent, selective, and orally bioavailable inhibitor of aggrecanase.
Subject(s)
Asparagine/chemical synthesis , Endopeptidases/metabolism , Hydroxamic Acids/chemical synthesis , Protease Inhibitors/chemical synthesis , Administration, Oral , Animals , Asparagine/analogs & derivatives , Asparagine/chemistry , Asparagine/pharmacokinetics , Asparagine/pharmacology , Biological Availability , Dogs , Drug Design , Endopeptidases/chemistry , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase 1/chemistry , Matrix Metalloproteinase 2/chemistry , Matrix Metalloproteinase 8/chemistry , Matrix Metalloproteinase 9/chemistry , Models, Molecular , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Protein Binding , Stereoisomerism , Structure-Activity RelationshipABSTRACT
PURPOSE: The effects of structural modifications on the membrane permeability of angiotensin II (Ang II) receptor antagonists and the usefulness of in vitro and in situ intestinal absorption models in predicting in vivo absorption or bioavailability were investigated. METHODS: Intestinal permeability was determined in vitro using Caco-2 cell monolayers and in situ using a perfused rat intestine method. Several physicochemical parameters were either measured or computed, and correlated with intestinal permeation. RESULTS: Permeation coefficients (Pa) across Caco-2 cell monolayers correlated well with both in situ absorption rate constants (ka) and in vivo bioavailability or % absorption. For these Ang II antagonists, Pa values larger than 3 x 10(-6) cm sec-1 and in situ ka values of 2 x 10(-4) min-1 cm-1 or above were associated with good in vivo absorption. Structural modifications at the R5 position, where a COOH group was substituted with either a CHO or CH2OH group, enhanced the permeability of the Ang II receptor antagonists up to 100-fold. There were good correlations between permeability and log P(octanol/buffer), log PHPLC, charge, solvation/desolvation energy and assigned hydrogen bonding potential. CONCLUSIONS: The correlations obtained in this study indicate that both the Caco-2 cell model and the in situ perfused rat intestine could be used to predict intestinal absorption in vivo. Structural modifications of the Ang II antagonists had a significant impact on the intestinal permeability. Charge, solvation energy, and hydrogen bonding are predominant determinants of intestinal permeability and oral bioavailability of these compounds.
