Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Jun 6

PMID 24900852

Citations 77

Authors

Lee D Fader

Eric Malenfant

Mathieu Parisien

Rebekah Carson

Francois Bilodeau

Serge Landry

Marc Pesant

Christian Brochu

Sebastien Morin

Catherine Chabot

Ted Halmos

Yves Bousquet

Murray D Bailey

Stephen H Kawai

Rene Coulombe

Steven Laplante

Araz Jakalian

Punit K Bhardwaj

Dominik Wernic

Patricia Schroeder

Maan Amad

Paul Edwards

Michel Garneau

Jianmin Duan

Michael Cordingley

Richard Bethell

Stephen W Mason

Michael Bos

Pierre Bonneau

Marc-Andre Poupart

Anne-Marie Faucher

Bruno Simoneau

Craig Fenwick

Christiane Yoakim

Youla Tsantrizos

Affiliations

Soon will be listed here.

Abstract

An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.

Citing Articles

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