title: 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 and human UDP glucuronosyl transferases (UGTs). The prodrug of inhibitor 2, i.e., compound 10, was found to possess remarkable anti-HIV-1 activity in cell culture (EC(50) 9 ± 4 nM, CC(50) 135 ± 7 μM, therapeutic index = 15,000).
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences and the Center for Drug Discovery, University of Georgia, Athens, GA 30602, USA.
authors.forename: Byung I
authors.initials: BI
authors.lastname: Seo
authors.forename: Vinod R
authors.initials: VR
authors.lastname: Uchil
authors.forename: Maurice
authors.initials: M
authors.lastname: Okello
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mishra
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Ma
authors.forename: Malik
authors.initials: M
authors.lastname: Nishonov
authors.forename: Qingning
authors.initials: Q
authors.lastname: Shu
authors.forename: Guochen
authors.initials: G
authors.lastname: Chi
authors.forename: Vasu
authors.initials: V
authors.lastname: Nair