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  3. Design and synthesis of novel fluorene derivatives as inhibitors of pyruvate dehydrogenase kinase

Design and synthesis of novel fluorene derivatives as inhibitors of pyruvate dehydrogenase kinase

  • Bioorg Med Chem Lett. 2024 Sep 1:109:129839. doi: 10.1016/j.bmcl.2024.129839.
Masafumi Inoue 1,  Hironobu Nagamori 2,  Toru Morita 2,  Satoru Kobayashi 2,  Koichi Suzawa 2,  Yuki Kitao 2,  Tomoyuki Saito 2,  Iichiro Kawahara 2,  Takuya Orita 2,  Shota Akai 2,  Tsuyoshi Adachi 2,  Takahisa Motomura 2
Affiliations

Affiliations

  • 1 Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. Electronic address: masafumi.inoue@jt.com.
  • 2 Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
PMID: 38844173 DOI: 10.1016/j.bmcl.2024.129839
Abstract

Activation of pyruvate dehydrogenase (PDH) by inhibition of pyruvate dehydrogenase kinase (PDHK) has the potential for the treatment of diabetes mellitus and its complications, caused by the malfunction of the glycolytic system and glucose oxidation. In this paper, we describe the identification of novel PDHK inhibitors with a fluorene structure. High-throughput screening using our in-house library provided compound 6 as a weak inhibitor that occupied the allosteric lipoyl group binding site in PDHK2. Structure-based drug design (SBDD) while addressing physicochemical properties succeeded in boosting inhibitory activity approximately 700-fold. Thus obtained compound 32 showed favorable pharmacokinetics profiles supported by high membrane permeability and metabolic stability, and exhibited activation of PDH in rat livers and a glucose lowering effect in Zucker fatty rats.

Keywords

Fluorene; Pyruvate dehydrogenase activation; Pyruvate dehydrogenase kinase inhibitor.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162586
    pyruvate dehydrogenase kinase inhibitor