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

التفاصيل البيبلوغرافية
العنوان: Synthesis and evaluation of an orally available "Y"-shaped biaryl peroxisome proliferator-activated receptor δ agonist.
المؤلفون: Kim DS; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Lee J; The Center for Marine Natural Products and Drug Discovery, School of Earth and Environmental Sciences, Seoul National University, NS-80, Seoul 151-747, Republic of Korea., Londhe AM; Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea., Kadayat TM; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Joo J; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Hwang H; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Kim KH; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea., Pae AN; Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea., Chin J; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea. Electronic address: jwchin@dgmif.re.kr., Cho SJ; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea. Electronic address: sjcho@dgmif.re.kr., Kang H; The Center for Marine Natural Products and Drug Discovery, School of Earth and Environmental Sciences, Seoul National University, NS-80, Seoul 151-747, Republic of Korea; Research Institute of Oceanography, Seoul National University, NS-80, Seoul 151-747, Republic of Korea. Electronic address: hjkang@snu.ac.kr.
المصدر: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 Aug 15; Vol. 26 (15), pp. 4382-4389. Date of Electronic Publication: 2018 Jul 20.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Elsevier Science
Original Publication: Oxford : New York : Pergamon Press, c1993-
مواضيع طبية MeSH: Acetates/*chemistry , Biphenyl Compounds/*chemical synthesis , PPAR delta/*agonists, Acetates/chemical synthesis ; Acetates/pharmacokinetics ; Administration, Oral ; Animals ; Binding Sites ; Biphenyl Compounds/chemistry ; Biphenyl Compounds/pharmacology ; Crystallography, X-Ray ; Drug Design ; Half-Life ; Humans ; Inhibitory Concentration 50 ; Mice ; Microsomes/metabolism ; Molecular Docking Simulation ; PPAR delta/metabolism ; Protein Structure, Tertiary ; Rats ; Stereoisomerism ; Structure-Activity Relationship ; Thiazoles/chemistry ; Thiazoles/metabolism
مستخلص: In this study, we designed and synthesized several novel "Y"-shaped biaryl PPARδ agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC 50 of 2.6 nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC 50  = 0.7 nM) shows much more potent activity than S isomer (EC 50  = 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 PPARδ agonist 3a is a viable drug candidate for the treatment of various PPARδ-related disorders.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
فهرسة مساهمة: Keywords: ADMET; Nuclear receptors; PK; PPARδ; Structure-activity relationship (SAR)
المشرفين على المادة: 0 (Acetates)
0 (Biphenyl Compounds)
0 (GW 501516)
0 (PPAR delta)
0 (Thiazoles)
تواريخ الأحداث: Date Created: 20180729 Date Completed: 20190225 Latest Revision: 20190225
رمز التحديث: 20240829
DOI: 10.1016/j.bmc.2018.06.044
PMID: 30054191
قاعدة البيانات: MEDLINE
الوصف
تدمد:1464-3391
DOI:10.1016/j.bmc.2018.06.044