181633-37-4Relevant academic research and scientific papers
Discovery of 1-(3-aryl-4-chlorophenyl)-3-(p-aryl)urea derivatives against breast cancer by inhibiting PI3K/Akt/mTOR and Hedgehog signalings
Li, Wenlu,Sun, Qinsheng,Song, Lu,Gao, Chunmei,Liu, Feng,Chen, Yuzong,Jiang, Yuyang
, p. 721 - 733 (2017/11/01)
PI3K/Akt/mTOR and hedgehog (Hh) signalings are two important pathways in breast cancer, which are usually connected with the drug resistance and cancer migration. Many studies indicated that PI3K/Akt/mTOR inhibitors and Hh inhibitors displayed synergistic effects, and the combination of the two signaling drugs could delay drug resistance and inhibit cancer migration in breast cancer. Therefore, the development of molecules simultaneously inhibiting these two pathways is urgent needed. Based on the structures of PI3K inhibitor buparlisib and Hh inhibitor vismodegib, a series of hybrid structures were designed and synthesized utilizing rational drug design and computer-based drug design. Several compounds displayed excellent antiproliferative activities against several breast cancer cell lines, including triple-negative breast cancer (TNBC) MDA-MB-231 cell. Further mechanistic studies demonstrated that the representative compound 9i could inhibit both PI3K/Akt/mTOR and hedgehog (Hh) signalings by inhibiting the phosphorylation of S6K and Akt as well as decreasing the SAG elevated expression of Gli1. Compound 9i could also induce apoptosis remarkably in T47D and MDA-MB-231 cells. In the transwell assay, 9i showed significant inhibition on the migration of MDA-MB-231.
Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: Identification of 5-methyl-1-[[2-[(2-methyl-3- pyridyl)oxy]5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent
Bromidge, Steven M.,Dabbs, Steven,Davies, David T.,Davies, Susannah,Duckworth, D. Malcolm,Forbes, Ian T.,Gaster, Laramie M.,Ham, Peter,Jones, Graham E.,King, Frank D.,Mulholland, Keith R.,Saunders, Damian V.,Wyman, Paul A.,Blaney, Frank E.,Clarke, Stephen E.,Blackburn, Thomas P.,Holland, Vicky,Kennett, Guy A.,Lightowler, Sean,Middlemiss, Derek N.,Trail, Brenda,Riley, Graham J.,Wood, Martyn D.
, p. 1123 - 1134 (2007/10/03)
The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5- HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.
