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

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.

SUBMITTER: Fader LD 

PROVIDER: S-EPMC4027581 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

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  

ACS medicinal chemistry letters 20140122 4

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 pot  ...[more]

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