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

[Display omitted] 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...

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Published in:Bioorganic & medicinal chemistry letters 2024-09, Vol.109, p.129839, Article 129839
Main Authors: Inoue, Masafumi, Nagamori, Hironobu, Morita, Toru, Kobayashi, Satoru, Suzawa, Koichi, Kitao, Yuki, Saito, Tomoyuki, Kawahara, Iichiro, Orita, Takuya, Akai, Shota, Adachi, Tsuyoshi, Motomura, Takahisa
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Language:English
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Fluorene
Pyruvate dehydrogenase activation
Pyruvate dehydrogenase kinase inhibitor
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container_title Bioorganic & medicinal chemistry letters
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creator Inoue, Masafumi
Nagamori, Hironobu
Morita, Toru
Kobayashi, Satoru
Suzawa, Koichi
Kitao, Yuki
Saito, Tomoyuki
Kawahara, Iichiro
Orita, Takuya
Akai, Shota
Adachi, Tsuyoshi
Motomura, Takahisa
description [Display omitted] 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.
doi_str_mv 10.1016/j.bmcl.2024.129839
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subjects Fluorene
Pyruvate dehydrogenase activation
Pyruvate dehydrogenase kinase inhibitor
title Design and synthesis of novel fluorene derivatives as inhibitors of pyruvate dehydrogenase kinase
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