Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1.
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.
['Fader|Lee D|LD|', 'Malenfant|Eric|E|', 'Parisien|Mathieu|M|', 'Carson|Rebekah|R|', 'Bilodeau|François|F|', 'Landry|Serge|S|', 'Pesant|Marc|M|', 'Brochu|Christian|C|', 'Morin|Sébastien|S|', 'Chabot|Catherine|C|', 'Halmos|Ted|T|', 'Bousquet|Yves|Y|', 'Bailey|Murray D|MD|', 'Kawai|Stephen H|SH|', 'Coulombe|René|R|', 'LaPlante|Steven|S|', 'Jakalian|Araz|A|', 'Bhardwaj|Punit K|PK|', 'Wernic|Dominik|D|', 'Schroeder|Patricia|P|', "Amad|Ma'an|M|", 'Edwards|Paul|P|', 'Garneau|Michel|M|', 'Duan|Jianmin|J|', 'Cordingley|Michael|M|', 'Bethell|Richard|R|', 'Mason|Stephen W|SW|', 'Bös|Michael|M|', 'Bonneau|Pierre|P|', 'Poupart|Marc-André|MA|', 'Faucher|Anne-Marie|AM|', 'Simoneau|Bruno|B|', 'Fenwick|Craig|C|', 'Yoakim|Christiane|C|', 'Tsantrizos|Youla|Y|']
NCINI HIV Integrase LTR DNA 3′-processing allosteric inhibitor