Discovery of the therapeutic potential of PPARδ agonist bearing 1,3,4- thiadiazole in inflammatory disorders.

Autor: Kim J; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea; BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy, Kyungpook National University, Daegu, 41566, Republic of Korea., Kadayat TM; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea., Lee JE; Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea., Kwon S; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea., Jung K; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea., Hwang JS; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea., Kwon OB; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea., Kim YJ; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea., Choi YK; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea., Park KG; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea., Hwang H; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea., Cho SJ; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea. Electronic address: sjcho@cureverse.co.kr., Lee T; BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy, Kyungpook National University, Daegu, 41566, Republic of Korea. Electronic address: tlee@knu.ac.kr., Jeon YH; Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea. Electronic address: jeon9014@gmail.com., Chin J; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea. Electronic address: jwchin@cureverse.co.kr.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Dec 05; Vol. 279, pp. 116856. Date of Electronic Publication: 2024 Sep 12.
DOI: 10.1016/j.ejmech.2024.116856
Abstrakt: As a defense mechanism against deleterious stimuli, inflammation plays a vital role in the development of many disorders, including atherosclerosis, inflammatory bowel disease, experimental autoimmune encephalomyelitis, septic and non-septic shock, and non-alcoholic fatty liver disease (NAFLD). Despite the serious adverse effects of extended usage, traditional anti-inflammatory medications, such as steroidal and non-steroidal anti-inflammatory medicines (NSAIDs), are commonly used for alleviating symptoms of inflammation. The PPARδ subtype of peroxisome proliferator-activated receptors (PPARs) has attracted interest because of its potential for reducing inflammation and related disorders. In this study, a series of 1,3,4-thiadiazole derivatives were designed, synthesized, and evaluated. Compound 11 exhibited potent PPARδ agonistic activity with EC 50 values 20 nM and strong selectivity over PPARα and PPARγ. Furthermore, compound 11 demonstrated favorable in vitro and in vivo pharmacokinetic properties. In vivo experiments using labeled macrophages and paw thickness measurements confirmed compound 11's potential to reduce macrophage infiltration and alleviate inflammation. These findings highlight compound 11 as a potent and promising therapeutic candidate for the treatment of acute inflammatory diseases and warrant further investigation to explore various biological roles.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jungwook chin reports financial support was provided by National Research Foundation of Korea. Taeho Lee reports financial support was provided by National Research Foundation of Korea. Jungwook chin has patent #PCT/KR2023/003210 pending to Daegu-Gyeongbuk Medical Innovation Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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