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

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.OAIID:RECH_ACHV_DSTSH_NO:T201810706RECH_ACHV_FG:RR00200001ADJUST_YN:EMP_ID:A000128CITE_RATE:2.442DEPT_NM:지구환경과학부EMAIL:[email protected]_YN:YN

A Series of Novel Terpyridine-Skeleton Molecule Derivants Inhibit Tumor Growth and Metastasis by Targeting Topoisomerases

A series of novel terpyridine-skeleton molecules containing conformational rigidity, 14 containing benzo­[4,5]­furo­[3,2-<i>b</i>]­pyridine core and 15 comprising chromeno­[4,3-<i>b</i>]­pyridine core, were synthesized, and their biological activities were evaluated. 3-(4-Phenylbenzo­[4,5]­furo­[3,2-<i>b</i>]­pyridin-2-yl)­phenol (<b>8</b>) was determined to be a nonintercalative topo I and II dual catalytic inhibitor and 3-(4-phenylchromeno­[4,3-<i>b</i>]­pyridine-2-yl)­phenol (<b>22</b>) was determined to be a nonintercalative topo IIα specific catalytic inhibitor by various assays. These two catalytic inhibitors induced apoptosis in addition to G1 arrest in T47D human breast cancer cells with much less DNA toxicity than etoposide. Compounds <b>8</b> and <b>22</b> significantly inhibited tumor growth in HCT15 subcutaneously implanted xenografted mice. The modification of compounds <b>8</b> and <b>22</b> with the introduction of a methoxy instead of a hydroxy group enhanced endogenous topo inhibitory activity, metabolic stability in diverse types of liver microsomes and improved pharmacokinetic parameters in rat plasma such as augmentation of bioavailability (41.3% and 33.2% for 2-(3-methoxyphenyl)-4-phenyl­benzofuro­[3,2-<i>b</i>]­pyridine (<b>8-M</b>) and 3-(4-phenyl­chromeno­[4,3-<i>b</i>]­pyridine-2-yl)­methoxybenzene (<b>22-M</b>), respectively)