2. Academic Validation
  3. Discovery of a potent, orally available furopyridine derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor

Discovery of a potent, orally available furopyridine derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor

  • Bioorg Med Chem Lett. 2024 Sep 1:109:129848. doi: 10.1016/j.bmcl.2024.129848.
Shuichi Hagihara 1,  Kouhei Ishizawa 2,  Manami Kikuchi 2,  Yuko Kawano 2,  Akiko Nishidate 2,  Fumi Matsumoto 2,  Naohiro Hashimoto 2,  Chiduko Sasaki 2,  Ikuko Miyaguchi 2,  Okimasa Okada 2,  Tomoya Akashi 2,  Shinji Nakayama 2,  Yuko Ogasawara 2,  Junichi Endo 3
Affiliations

Affiliations

  • 1 Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. Electronic address: hagihara.shuuichi@ma.mt-pharma.co.jp.
  • 2 Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
  • 3 Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. Electronic address: endoh.junichi@mb.mt-pharma.co.jp.
PMID: 38876176 DOI: 10.1016/j.bmcl.2024.129848
Abstract

We explored novel immunosuppressive agents with immune tolerance using a phenotypic drug discovery strategy, focusing on costimulatory molecules in T cells, and obtained triazolothienodiazepine derivatives. Their mechanism of action is to inhibit the bromodomain and extra-terminal domain (BET) family, as we have previously reported. Selective inhibition of the first bromodomain (BD1) of the BET family is expected to exert antitumor and immunosuppressive effects, similar to BET inhibitors. This study identified furopyridine derivatives 7 and 8 with high BD1 inhibitory activity and high selectivity over BD2. Compound 7 was found to be orally bioavailable and exhibited anti-inflammatory activity in a lipopolysaccharide-induced model.

Keywords

BD1 selectivity; BET family; Furopyridine; Inflammation; Orally available; X-ray crystallography.

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