Impact of passive permeability and gut efflux transport on the oral bioavailability of novel series of piperidine-based renin inhibitors in rodents

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5547-51. doi: 10.1016/j.bmcl.2011.06.095. Epub 2011 Jun 28.

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B / deficiency
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Administration, Oral
  • Animals
  • Biological Availability
  • Biological Transport / drug effects
  • Cell Membrane Permeability / drug effects*
  • Dose-Response Relationship, Drug
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Piperidines / administration & dosage
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Rats
  • Renin / antagonists & inhibitors*
  • Renin / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Piperidines
  • piperidine
  • multidrug resistance protein 3
  • Renin