Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10594149 | Bioorganic & Medicinal Chemistry Letters | 2011 | 5 Pages |
Abstract
An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low Fpo of pyridone analogs was shown to be caused by a combination of poor passive permeability and gut efflux transport. Substitution of pyridone ring for a more lipophilic moiety (log D >1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (Papp >10 Ã 10â6 cm/s), which contributed to overwhelm gut transporters and increase rat Fpo. Log D and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors.
Related Topics
Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Jean-François Lévesque, Kelly Bleasby, Amandine Chefson, Austin Chen, Daniel Dubé, Yves Ducharme, Pierre-André Fournier, Sébastien Gagné, Michel Gallant, Erich Grimm, Michael Hafey, Yongxin Han, Robert Houle, Patrick Lacombe, Sébastien Laliberté,