کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
10595594 981873 2013 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
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
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
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
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 23, Issue 13, 1 July 2013, Pages 3967-3975
نویسندگان
, , , , , , , , , , , , , , ,