Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases

被引：19

作者：

Lee, Dahye ^{[1
]}

Pagire, Haushabhau S. ^{[1
]}

Pagire, Suvarna H. ^{[1
]}

Bae, Eun Jung ^{[1
]}

Dighe, Mahesh ^{[1
]}

Kim, Minhee ^{[1
]}

Lee, Kyu Myung ^{[2
]}

Jang, Yoon Kyung ^{[2
]}

Jaladi, Ashok Kumar ^{[2
]}

Jung, Kwan-Young ^{[2
]}

Yoo, Eun Kyung ^{[3
]}

Gim, Hee Eon ^{[3
]}

Lee, Seungmi ^{[3
]}

Choi, Won-Il ^{[3
]}

Chi, Young-In ^{[3
]}

Song, Jin Sook ^{[2
]}

Bae, Myung Ae ^{[2
]}

Jeon, Yong Hyun ^{[3
]}

Lee, Ga-Hyun ^{[5
]}

Liu, Kwang-Hyeon ^{[4
,5
]}

Lee, Taeho ^{[5
]}

Park, Sungmi ^{[3
]}

Jeon, Jae-Han ^{[3
,6
]}

Lee, In-Kyu ^{[3
,6
]}

Ahn, Jin Hee ^{[1
]}

机构：

[1] Gwangju Inst Sci & Technol, Dept Chem, Gwangju 61005, South Korea

[2] Korea Res Inst Chem Technol, Bio & Drug Discovery Div, Daejeon 34114, South Korea

[3] Kyungpook Natl Univ Hosp, Leading Edge Res Ctr Drug Discovery & Dev Diabet, Daegu 41404, South Korea

[4] Daegu Gyeongbuk Med Innovat Fdn, Lab Anim Ctr, Daegu 41061, South Korea

[5] Kyungpook Natl Univ, Res Inst Pharmaceut Sci, Coll Pharm, Daegu 41566, South Korea

[6] Kyungpook Natl Univ, Kyungpook Natl Univ Hosp, Dept Internal Med, Sch Med, Daegu 41944, South Korea

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 02期

基金：

新加坡国家研究基金会;

关键词：

CELL ACTIVATION; STARVATION; GLUCOSE; P53; PATHOGENESIS; CISPLATIN; PATHWAYS; SYSTEM; GROWTH;

D O I：

10.1021/acs.jmedchem.8b01168

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pyruvate dehydrogenase kinase 4 (PDK4) activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. Structural modifications of hit anthraquinone led to the identification of a new series of allosteric PDK4 inhibitors. Among this series, compound 8c showed promising in vitro activity with an IC50 value of 84 nM. Good metabolic stability, pharmacokinetic profiles, and possible metabolites were suggested. Compound 8c improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in a passive cutaneous anaphylaxis mouse model. Additionally, compound 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis. From the molecular docking studies, compound 8c displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development toward PDK4 inhibitors.

引用

页码：575 / 588

页数：14

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