Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV‑1 Integrase Inhibitors

The standard of care for HIV-1 infection,
highly active antiretroviral
therapy (HAART), combines two or more drugs from at least two classes.
Even with the success of HAART, new drugs with novel mechanisms are
needed to combat viral resistance, improve adherence, and mitigate
toxicities. Active site inhibitors of HIV-1 integrase are clinically
validated for the treatment of HIV-1 infection. Here we describe allosteric
inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction
site and disrupt the structure of the integrase multimer that is required
for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors
was developed with a vector in the 2-position that was optimized by
structure-guided compound design. This resulted in the discovery of
pyrazolopyrimidine 3, which was optimized at the 2- and
7-positions to afford 26 and 29 as potent
allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar
antiviral potency in cell culture and encouraging PK properties.