Discovery of Potent HIV-1 Capsid Assembly Inhibitors
Discovery of Potent HIV-1 Capsid Assembly Inhibitors
Discovery of Potent HIV-1 Capsid Assembly Inhibitors
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High Throughput Screening (HTS)<br />
and hit analysis<br />
Several chemically distinct clusters <strong>of</strong> selective hits (chemotypes) were obtained<br />
– 2 chemotypes were chosen for Lead Optimization based on multiple<br />
parameters including:<br />
– NMR and co-crystallography inhibitors bound to CA-NTD<br />
BI 257 BI 060<br />
O<br />
H<br />
N<br />
F<br />
F<br />
F<br />
N<br />
N<br />
O<br />
O<br />
N<br />
N<br />
OH<br />
O<br />
N<br />
N<br />
O<br />
N<br />
N<br />
F<br />
HO<br />
O<br />
N<br />
EC 50<br />
:<br />
Benzodiazepines (BD)<br />
70 ± 30nM (n=21)<br />
Benzimidazoles (BIM)<br />
– Resistance selection & Mode-<strong>of</strong>-Action (MoA) studies were performed<br />
– MoA was consistent with inhibition <strong>of</strong> capsid assembly<br />
Boehringer Ingelheim - CROI 2010 5<br />
F<br />
62 ± 23 nM (n=53)<br />
CC 50<br />
: >28μM ≥20μM<br />
F
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