title: Impact of passive permeability and gut efflux transport on the oral bioavailability of novel series of piperidine-based renin inhibitors in rodents.
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.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1. levesqjf@videotron.ca
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lévesque
authors.forename: Kelly
authors.initials: K
authors.lastname: Bleasby
authors.forename: Amandine
authors.initials: A
authors.lastname: Chefson
authors.forename: Austin
authors.initials: A
authors.lastname: Chen
authors.forename: Daniel
authors.initials: D
authors.lastname: Dubé
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Fournier
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gagné
authors.forename: Michel
authors.initials: M
authors.lastname: Gallant
authors.forename: Erich
authors.initials: E
authors.lastname: Grimm
authors.forename: Michael
authors.initials: M
authors.lastname: Hafey
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Han
authors.forename: Robert
authors.initials: R
authors.lastname: Houle
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacombe
authors.forename: Sébastien
authors.initials: S
authors.lastname: Laliberté
authors.forename: Dwight
authors.initials: D
authors.lastname: MacDonald
authors.forename: Bruce
authors.initials: B
authors.lastname: Mackay
authors.forename: Robert
authors.initials: R
authors.lastname: Papp
authors.forename: Richard
authors.initials: R
authors.lastname: Tschirret-Guth
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012083:Renin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D010880:Piperidines; D012083:Renin; D000092502:Renin Inhibitors; C032727:piperidine; C095122:multidrug resistance protein 3