HIV-1 integrase is a virally encoded enzyme essential for replication. Since diketo acid inhibitors were identified many efforts have been directed toward the discovery of integrase strand transfer inhibitors (INSTi). These efforts have culminated in the discovery of raltegravir, the first marketed HIV-1 INSTi. However, there is significant opportunity for improvement including overall dose burden, dosing interval and potency against resistant viruses. By using a two-metal pharmacophore based design strategy, a core carbamoyl pyridone motif was constructed to effectively coordinate two magnesium cofactors while templating an aromatic group into a hydrophobic pharmacophore space. The series exhibited potent antiviral activity with promising DMPK properties. Optimization of this series led to the discovery of dolutegravir which demonstrated the sought after differentiation and improvements over existing drugs.

Two-metal pharmacophore design strategy utilized discovery of carbamoyl pyridone integrase inhibitors

244th National Meeting (2012)

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