1. Impact of passive permeability and gut efflux transport on the oral bioavailability of novel series of piperidine-based renin inhibitors in rodents
- Author
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Kelly Bleasby, Dwight Macdonald, Bruce Mackay, Richard Tschirret-Guth, Robert Houle, Sebastien Laliberte, Patrick Lacombe, Robert Papp, Erich L. Grimm, Amandine Chefson, Jean-François Lévesque, Michael J. Hafey, Pierre-André Fournier, Sébastien Gagné, Yongxin Han, Yves Ducharme, Michel Gallant, Austin Chen, and Daniel Dube
- Subjects
ATP Binding Cassette Transporter, Subfamily B ,Cell Membrane Permeability ,Clinical Biochemistry ,Administration, Oral ,Biological Availability ,Pharmaceutical Science ,ATP-binding cassette transporter ,Absorption (skin) ,Pharmacology ,Biochemistry ,Mice ,Structure-Activity Relationship ,Piperidines ,Renin ,Drug Discovery ,Renin–angiotensin system ,Animals ,Structure–activity relationship ,Molecular Biology ,Mice, Knockout ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Biological Transport ,Stereoisomerism ,Transporter ,Rats ,Bioavailability ,Permeability (electromagnetism) ,Molecular Medicine ,Efflux - Abstract
An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low F(po) 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 (logD>1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (P(app)>10 × 10(-6) cm/s), which contributed to overwhelm gut transporters and increase rat F(po). LogD and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors.
- Published
- 2011
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