title: Identification of potent and orally bioavailable nucleotide competing reverse transcriptase inhibitors: in vitro and in vivo optimization of a series of benzofurano[3,2-d]pyrimidin-2-one derived inhibitors.
abstract: Recently, a new class of HIV reverse transcriptase (HIV-RT) inhibitors has been reported. The novel mechanism of inhibition by this class involves competitive binding to the active site of the RT enzyme and has been termed Nucleotide-Competing Reverse Transcriptase Inhibitors (NcRTIs). In this publication we describe the optimization of a novel benzofurano[3,2-d]pyrimidin-2-one series of NcRTIs. The starting point for the current study was inhibitor 2, which had high biochemical and antiviral potency but only moderate permeability in a Caco-2 assay and high B-to-A efflux, resulting in moderate rat bioavailability and low Cmax. We present herein the results and strategies we employed to optimize both the potency as well as the permeability, metabolic stability and pharmacokinetic profile of this series. One of the key observations of the present study was the importance of shielding polar functionality, at least in the context of the current chemotype, to enhance permeability. These studies led to the identification of inhibitors 39 and 45, which display sub-nanomolar antiviral potency in a p24 ELISA assay with significantly reduced efflux ratios (ratios <1.5). These inhibitors also display excellent rat pharmacokinetic profiles with high bioavailabilities and low clearance.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5.
authors.forename: Claudio F
authors.initials: CF
authors.lastname: Sturino
authors.forename: Yves
authors.initials: Y
authors.lastname: Bousquet
authors.forename: Clint A
authors.initials: CA
authors.lastname: James
authors.forename: Patrick
authors.initials: P
authors.lastname: DeRoy
authors.forename: Martin
authors.initials: M
authors.lastname: Duplessis
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Edwards
authors.forename: Ted
authors.initials: T
authors.lastname: Halmos
authors.forename: Joannie
authors.initials: J
authors.lastname: Minville
authors.forename: Louis
authors.initials: L
authors.lastname: Morency
authors.forename: Sébastien
authors.initials: S
authors.lastname: Morin
authors.forename: Bounkham
authors.initials: B
authors.lastname: Thavonekham
authors.forename: Martin
authors.initials: M
authors.lastname: Tremblay
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
authors.forename: Maria
authors.initials: M
authors.lastname: Ribadeneira
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.forename: Alex
authors.initials: A
authors.lastname: Pelletier
authors.forename: Sonia
authors.initials: S
authors.lastname: Tremblay
authors.forename: Louie
authors.initials: L
authors.lastname: Lamorte
authors.forename: Richard
authors.initials: R
authors.lastname: Bethell
authors.forename: Michael G
authors.initials: MG
authors.lastname: Cordingley
authors.forename: Daniel
authors.initials: D
authors.lastname: Rajotte
authors.forename: Bruno
authors.initials: B
authors.lastname: Simoneau
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D006678:HIV / Q000187:drug effects*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011744:Pyrimidinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase