2. Academic Validation
  3. Discovery of tricyclic HIV-1 integrase-LEDGF/p75 allosteric inhibitors by intramolecular direct arylation reaction

Discovery of tricyclic HIV-1 integrase-LEDGF/p75 allosteric inhibitors by intramolecular direct arylation reaction

  • Bioorg Med Chem Lett. 2022 May 15:64:128664. doi: 10.1016/j.bmcl.2022.128664.
Yoshiyuki Taoda 1,  Toshiyuki Akiyama 2,  Kenji Tomita 2,  Misato Fujiwara-Kitamura 2,  Yoshinori Tamura 2,  Takashi Kawasuji 2,  Eriko Matsuoka 2,  Erika Akihisa 2,  Takahiro Seki 2,  Tomokazu Yoshinaga 2
Affiliations

Affiliations

  • 1 Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan. Electronic address: yoshiyuki.taoda@shionogi.co.jp.
  • 2 Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
PMID: 35272008 DOI: 10.1016/j.bmcl.2022.128664
Abstract

We have been conducting exploratory research to develop human immunodeficiency virus type-1 (HIV-1) integrase-LEDGF/p75 allosteric inhibitors (INLAIs). Here, we report on a newly designed compound with a tricyclic scaffold that shows promise as an inhibitor. Various scaffolds were synthesized by intramolecular direct arylation reaction to fix the position of a lipophilic side chain required for Antiviral activity. Among these, the compound having an N-mesyl dihydrophenanthridine ring showed the best Antiviral activity. Compound 42i, prepared by side chain optimization of the C-4 and C-6 positions, exhibited high Antiviral activity against wild-type (WT) and the T174I mutant (EC50 (WT) = 4.6 nM, EC50 (T174I) = 83 nM) with a good PK profile. Based on co-crystal structural analysis of compound 42i and WT HIV-1 IN CCD, we discuss the interaction important for high Antiviral activity.

Keywords

Allosteric inhibitor; Dihydrophenanthridine; Direct arylation; HIV-1; INLAIs; Integrase; LEDGF/p75.

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