Development of the next generation of HIV-1 integrase inhibitors: pyrazolone as a novel inhibitor scaffold.
HIV-1 integrase (IN), one of the essential enzymes in HIV infection, has been validated as a target for HIV treatment. While more than 20 drugs have been approved by the FDA to treat HIV/AIDS, only one drug, Raltegravir (1), was approved as an IN inhibitor. The rapid mutation of the virus, which leads to multidrug resistant HIV strains, presents an urgent need to find potent compounds that can serve as second-generation IN inhibitors. The pyrazolone scaffold, predicted by a computational modeling study using GS-9137(2) as a pharmacophoric model, has shown to inhibit the IN catalytic activities in low micromolar range. We have synthesized various analogs based on the pyrazolone scaffold and performed SAR studies. This paper will showcase the up-to-date result of this scaffold as a promising HIV-1 IN inhibitor.
Hadi
Victor
V
Loker Hydrocarbon Research Institute, Department of Chemistry, University of Southern California, Los Angeles, CA 90089, United States.
Koh
Yung-Hyo
YH
Sanchez
Tino Wilson
TW
Barrios
Danielle
D
Neamati
Nouri
N
Jung
Kyung Woon
KW
D002384:Catalysis; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D047069:Pyrazolones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D019428:HIV Integrase Inhibitors; D047069:Pyrazolones; C038362:pyrazolone