125802-17-7Relevant academic research and scientific papers
Synthesis and in Vitro Anticancer Activity of the First Class of Dual Inhibitors of REV-ERBβ and Autophagy
Torrente, Esther,Parodi, Chiara,Ercolani, Luisa,De Mei, Claudia,Ferrari, Alessio,Scarpelli, Rita,Grimaldi, Benedetto
, p. 5900 - 5915 (2015/08/24)
Autophagy inhibition is emerging as a promising anticancer strategy. We recently reported that the circadian nuclear receptor REV-ERBβ plays an unexpected role in sustaining cancer cell survival when the autophagy flux is compromised. We also identified 4-[[[1-(2-fluorophenyl)cyclopentyl]amino]methyl]-2-[(4-methylpiperazin-1-yl)methyl]phenol, 1 (ARN5187), as a novel dual inhibitor of REV-ERBβ and autophagy. 1 had improved cytotoxicity against BT-474 breast cancer cells compared to chloroquine, a clinically relevant autophagy inhibitor. Here, we present the results of structure-activity studies, based around 1, that disclose the first class of dual inhibitors of REV-ERBβ and autophagy. This study led to identification of 18 and 28, which were more effective REV-ERBβ antagonists than 1 and were more cytotoxic to BT-474. The combination of optimal chemical and structural moieties of these analogs generated 30, which elicited 15-fold greater REV-ERBβ inhibitory and cytotoxic activities compared to 1. Furthermore, 30 induced death in a panel of tumor cell lines at doses 5-50 times lower than an equitoxic amount of chloroquine but did not affect the viability of normal mammary epithelial cells.
DIARYLALKYLAMINE REV-ERB ANTAGONISTS AND THEIR USE AS MEDICAMENTS
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Page/Page column 48; 63; 71, (2015/04/28)
The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof : It further discloses a pharmaceutical composition comprising the compounds of Formula (I) and their uses as anti-proliferative and pro-apoptotic agents for cancer therapy.
Synthesis and Anticonvulsant Activity of 1-Phenylcyclohexylamine Analogues
Thurkauf, Andrew,Costa, Brian de,Yamaguchi, Shun-ichi,Mattson, Mariena V.,Jacobson, Arthur E.,et al.
, p. 1452 - 1458 (2007/10/02)
Thirty-eight analogues of 1-phenylcyclohexylamine (PCA), a phencyclidine (PCP) derivative, were examined for their activities in the mouse maximal electroshock (MES) seizure test and in a motor-toxicity assay.In addition, we determined the binding affinities of the compounds for PCP acceptor sites in rat brain membranes labeled with -1-piperidine.Many of the analogues were protective against MES seizures (ED50s of 4-41 mg/kg, ip) and all of these compounds caused motor toxicity.The potencies in the motor toxicity and MES seizure tests showed a moderate correlation with the affinities for PCP sites.Several analogues exhibited a greater separation of potencies in the motor toxicity and MES seizure tests than did the parent compound PCA.These were obtained by (i) 3-methylation of the cyclohexyl ring trans to the phenyl ring, (ii) methoxylation at the ortho position on the phenyl ring, and (iii) contraction of the cyclohexane ring to form the corresponding cyclopentane.
