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Synthesis and evaluation of an orally available Y-shaped biaryl peroxisome proliferator-activated receptor δ agonist : Synthesis and evaluation of an orally available "Y"-shaped biaryl peroxisome proliferator-activated receptor delta agonist

Cited 5 time in Web of Science Cited 5 time in Scopus
Authors

Kim, Dong-Su; Lee, Jaehwan; Londhe, Ashwini M.; Kadayat, Tara Man; Joo, Jeongmin; Hwang, Hayoung; Kim, Kyung-Hee; Pae, Ae Nim; Chin, Jungwook; Cho, Sung Jin; Kang, Heonjoong

Issue Date
2018-08-15
Publisher
Pergamon Press Ltd.
Citation
Bioorganic and Medicinal Chemistry, Vol.26 No.15, pp.4382-4389
Abstract
In this study, we designed and synthesized several novel "Y"-shaped biaryl PPARS agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC50 of 2.6 nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC50 = 0.7 nM) shows much more potent activity than S isomer (EC50 = 6.1 nM). Molecular docking studies between the PPAR ligand binding domain and enantiospecific R and S isomers of compound 3a were performed. In vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) and in vivo PK profiles show that compound 3a possesses superior drug-like properties including good bioavailability. Our overall results clearly demonstrate that this orally administrable PPAR delta agonist 3a is a viable drug candidate for the treatment of various PPARS-related disorders.
ISSN
0968-0896
Language
English
URI
https://hdl.handle.net/10371/149742
DOI
https://doi.org/10.1016/j.bmc.2018.06.044
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