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

• Published in: ACS medicinal chemistry letters Vol. 5; no. 4; pp. 422 - 427
• Main Authors: Fader, Lee D, Malenfant, Eric, Parisien, Mathieu, Carson, Rebekah, Bilodeau, François, Landry, Serge, Pesant, Marc, Brochu, Christian, Morin, Sébastien, Chabot, Catherine, Halmos, Ted, Bousquet, Yves, Bailey, Murray D, Kawai, Stephen H, Coulombe, René, LaPlante, Steven, Jakalian, Araz, Bhardwaj, Punit K, Wernic, Dominik, Schroeder, Patricia, Amad, Ma’an, Edwards, Paul, Garneau, Michel, Duan, Jianmin, Cordingley, Michael, Bethell, Richard, Mason, Stephen W, Bös, Michael, Bonneau, Pierre, Poupart, Marc-André, Faucher, Anne-Marie, Simoneau, Bruno, Fenwick, Craig, Yoakim, Christiane, Tsantrizos, Youla
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.04.2014; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; HIV Integrase; LTR DNA 3′-processing; allosteric inhibitor; NCINI; MECHANISM; ERA; SMALL-MOLECULE INHIBITORS; LTR DNA 3 '-processing; BINDING-SITE; LEDGF/P75; IDENTIFICATION
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml500002n

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.