2. Academic Validation
  3. Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1

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

Affiliation

  • 1 Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
PMID: 24900852 DOI: 10.1021/ml500002n
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.

Figures
Products