Article ID Journal Published Year Pages File Type
10594149 Bioorganic & Medicinal Chemistry Letters 2011 5 Pages PDF
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 × 10−6 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
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