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

  • ACS Med Chem Lett. 2014 Jan 22;5(4):422-7. doi: 10.1021/ml500002n.
Lee D Fader  1 ,  Eric Malenfant  1 ,  Mathieu Parisien  1 ,  Rebekah Carson  1 ,  François Bilodeau  1 ,  Serge Landry  1 ,  Marc Pesant  1 ,  Christian Brochu  1 ,  Sébastien Morin  1 ,  Catherine Chabot  1 ,  Ted Halmos  1 ,  Yves Bousquet  1 ,  Murray D Bailey  1 ,  Stephen H Kawai  1 ,  René Coulombe  1 ,  Steven LaPlante  1 ,  Araz Jakalian  1 ,  Punit K Bhardwaj  1 ,  Dominik Wernic  1 ,  Patricia Schroeder  1 ,  Ma'an Amad  1 ,  Paul Edwards  1 ,  Michel Garneau  1 ,  Jianmin Duan  1 ,  Michael Cordingley  1 ,  Richard Bethell  1 ,  Stephen W Mason  1 ,  Michael Bös  1 ,  Pierre Bonneau  1 ,  Marc-André Poupart  1 ,  Anne-Marie Faucher  1 ,  Bruno Simoneau  1 ,  Craig Fenwick  1 ,  Christiane Yoakim  1 ,  Youla Tsantrizos  1
Affiliations
  • 1. Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
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.

Keywords
HIV Integrase; LTR DNA 3′-processing; NCINI; allosteric inhibitor.
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