| Literature DB >> 24900852 |
Lee D Fader1, Eric Malenfant1, Mathieu Parisien1, Rebekah Carson1, François Bilodeau1, Serge Landry1, Marc Pesant1, Christian Brochu1, Sébastien Morin1, Catherine Chabot1, Ted Halmos1, Yves Bousquet1, Murray D Bailey1, Stephen H Kawai1, René Coulombe1, Steven LaPlante1, Araz Jakalian1, Punit K Bhardwaj1, Dominik Wernic1, Patricia Schroeder1, Ma'an Amad1, Paul Edwards1, Michel Garneau1, Jianmin Duan1, Michael Cordingley1, Richard Bethell1, Stephen W Mason1, Michael Bös1, Pierre Bonneau1, Marc-André Poupart1, Anne-Marie Faucher1, Bruno Simoneau1, Craig Fenwick1, Christiane Yoakim1, Youla Tsantrizos1.
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.Entities:
Keywords: HIV Integrase; LTR DNA 3′-processing; NCINI; allosteric inhibitor
Year: 2014 PMID： 24900852 PMCID： PMC4027581 DOI： 10.1021/ml500002n
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345