ACS Medicinal Chemistry Letters · 2014 · 175 citations · 18 references
Hiv-1 IntegraseImmunologyMolecular BiologyPharmacotherapyBi 224436Antiviral DrugMedicinal ChemistryAntiviral Drug DevelopmentResistance Mutation (Virology)Compound 1BiochemistryHivPharmacologyAntiviral CompoundNatural SciencesAntiviral TherapyMedicineDrug DiscoveryLead Optimization
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.
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François Clavel, Allan J. Hance · New England Journal of Medicine · 2004 · 770 citations
Hiv Drug Resistance, Antiretroviral Therapy, Antiviral Compound +15