ACS Medicinal Chemistry Letters · 2014 · 180 citations · 18 references
PharmacyMedicinal ChemistryPharmacologyDrug DiscoveryLead OptimizationVirologyAntiviral PharmacologyEnzyme InhibitionHit-to-lead OptimizationLead DiscoveryLigand BindingPotency OptimizationAntiviral Drug DesignAntiviral Structure-activity RelationshipsIntegrase ProteinsIntegrase Strand Transfer InhibitorsNon-nucleoside Reverse Transcriptase InhibitorsNonnucleoside InhibitorsNucleoside Reverse Transcriptase InhibitorsQuinoline Chemistry
A 3′‑processing integrase assay was used to screen the Boehringer Ingelheim compound library. Hit‑to‑lead optimization revealed that C3/C4 substituents, the C7 position, and a quinoline at C4 are critical for potency and stability, culminating in the discovery of BI 224436, the first NCINI to enter a phase Ia trial.
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.
18