Discovery of a Potent HIV Integrase Inhibitor that Leads to a Prodrug with Significant anti-HIV Activity.

ABSTRACT: Worldwide research efforts in drug discovery involving HIV integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity and drug-drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC(50) 70 nM), strategically assembled on a pyridinone scaffold. A focused structure-activity investigation of this parent compound led to a significantly more potent ST inhibitor, 2 (IC(50) 6 ± 3 nM). Compound 2 exhibits good stability in pooled human liver microsomes. It also displays a notably favorable profile with respect to key human cytochrome P450 (CYP) isozymes a

SUBMITTER: Seo BI 

PROVIDER: S-EPMC3274775 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature