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 2024-01-19T22:02:46Z 2024-01-19T22:02:46Z 2021-09-03 2018-08-15 0968-0896 https://pubs.kist.re.kr/handle/201004/121036 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. English PERGAMON-ELSEVIER SCIENCE LTD GAMMA INVERSE AGONISTS PPAR-DELTA 4-HYDROXYTAMOXIFEN ANALOGS BIOLOGICAL EVALUATION METABOLIC SYNDROME DRUG DISCOVERY ALPHA ADIPOSE DYSLIPIDEMIA BETA/DELTA Synthesis and evaluation of an orally available "Y"-shaped biaryl peroxisome proliferator-activated receptor delta agonist Article 10.1016/j.bmc.2018.06.044 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.26, no.15, pp.4382 - 4389 BIOORGANIC & MEDICINAL CHEMISTRY 26 15 4382 4389 scie scopus 000443567500003 2-s2.0-85050270617 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article GAMMA INVERSE AGONISTS PPAR-DELTA 4-HYDROXYTAMOXIFEN ANALOGS BIOLOGICAL EVALUATION METABOLIC SYNDROME DRUG DISCOVERY ALPHA ADIPOSE DYSLIPIDEMIA BETA/DELTA Nuclear receptors PPAR delta Structure-activity relationship (SAR) ADMET PK