Discovery of novel integrase-LEDGF/p75 allosteric inhibitors based on a benzene scaffold

  • Bioorg Med Chem. 2020 Sep 1;28(17):115643. doi: 10.1016/j.bmc.2020.115643.
Shuichi Sugiyama  1 ,  Tsutomu Iwaki  2 ,  Yoshinori Tamura  2 ,  Kenji Tomita  2 ,  Eriko Matsuoka  2 ,  Shuhei Arita  2 ,  Takahiro Seki  2 ,  Tomokazu Yoshinaga  2 ,  Takashi Kawasuji  2
Affiliations
  • 1. Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited, 1-1, Futabacho, 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: [email protected].
  • 2. Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited, 1-1, Futabacho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
PMID: 32773094 DOI: 10.1016/j.bmc.2020.115643
Abstract

We report herein the discovery of novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a benzene scaffold 3. This scaffold can extend substituents from the C1 position unlike the common pyridine scaffolds 2. Structure-activity relationship studies showed that the sulfonamide linker at the C1 position was important for the Antiviral activity. Interaction between sulfonamide and Q95 was observed by X-ray crystallography. Compound 31h showed more potent Antiviral activity (EC50 (NL432) = 3.9 nM) than BI-224436 (EC50 (NL432) = 56 nM), suggesting the potential of the newly designed scaffold 3.

Keywords
HIV; INLAIs (integrase-LEDGF/p75 allosteric inhibitors); LEDGF (lens epithelium-derived growth factor).
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