Triketoacid inhibitors of HIV-integrase: A new chemotype useful for probing the integrase pharmacophore

• Published in: Bioorganic & medicinal chemistry letters 2006-06, Vol.16 (11), p.2920-2924
• Main Authors: Walker, Michael A., Johnson, Timothy, Ma, Zhuping, Banville, Jacques, Remillard, Roger, Kim, Oak, Zhang, Yunhui, Staab, Andrew, Wong, Henry, Torri, Albert, Samanta, Himadri, Lin, Zeyu, Deminie, Carol, Terry, Brian, Krystal, Mark, Meanwell, Nicholas
• Format: Article
• Language: English
• Subjects: AIDS; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Diketoacid; HIV Integrase - chemistry; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; HIV-integrase; Human immunodeficiency virus; Keto Acids - chemical synthesis; Keto Acids - chemistry; Keto Acids - pharmacology; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Structure-Activity Relationship; Triketoacid
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.03.010

This study reports on the discovery of a new triketoacid-based chemotype that selectively inhibits the strand transfer reaction of HIV-integrase. SAR studies showed that the template binds to integrase in a manner similar to the diketoacid-based inhibitors. Moreover, comparison of the new chemotype to two different diketoacid templates led us to propose two aryl-binding domains in the inhibitor binding site. This information was used to design a new diketoacid template with improved activity against the enzyme. Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. This study reports on the discovery of a new triketoacid-based chemotype that selectively inhibits the strand transfer reaction of HIV-integrase. SAR studies showed that the template binds to integrase in a manner similar to the diketoacid-based inhibitors. Moreover, comparison of the new chemotype to two different diketoacid templates led us to propose two aryl-binding domains in the inhibitor binding site. This information was used to design a new diketoacid template with improved activity against the enzyme.