- Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors
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The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50?=?467?nM, PARP-2 IC50?=?11.5?nM, selectivity PARP-1/PARP-2?=?40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program.
- Zhao, Hailong,Ji, Ming,Cui, Guonan,Zhou, Jie,Lai, Fangfang,Chen, Xiaoguang,Xu, Bailing
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- Discovery of a clinical stage multi-kinase inhibitor sodium (E)-2-{2-methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl] phenylamino}acetate (ON 01910.Na): Synthesis, structure-activity relationship, and biological activity
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Cyclin D proteins are elevated in many cancer cells, and targeted deletion of cyclin D1 gene in the mammary tissues protects mice from breast cancer. Accordingly, there is an increasing awareness of this novel nonenzymatic target for cancer therapeutics. We have developed novel, nonalkylating styrylbenzylsulfones that induce cell death in wide variety of cancer cells without affecting the proliferation and survival of normal cells. The development of derivatized styrylbenzylsulfones followed logically from a tumor cell cytotoxicity screen performed in our laboratory that did not have an a priori target profile. Modifications of some of the precursor molecules led to lead optimization with regard to tumor cell cytotoxicity. In this report we describe the synthesis and structure-activity relationships of novel, nonalkylating (E)-styrylbenzylsulfones and the development of the novel anticancer agent sodium (E)-2-{2-methoxy-5-[(2′,4′,6′- trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na), which is in phase III trials for myelodysplastic syndromes (MDS) associated with aberrant expression of cyclin D proteins.
- Reddy, M. V. Ramana,Venkatapuram, Padmavathi,Mallireddigari, Muralidhar R.,Pallela, Venkat R.,Cosenza, Stephen C.,Robell, Kimberly A.,Akula, Balaiah,Hoffman, Benjamin S.,Reddy, E. Premkumar
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experimental part
p. 6254 - 6276
(2011/11/01)
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- SUBSTITUTED IMIDAZOLONE DERIVATIVES, PREPARATIONS AND USES
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The present invention relates to polysubstituted imidazolone derivatives, to the pharmaceutical compositions comprising them and to the therapeutic uses thereof in the human and animal health fields. The present invention also relates to a process for preparing these derivatives.
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Page/Page column 65
(2010/02/16)
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- Potent dihydroquinolinone dopamine D2 partial agonist/serotonin reuptake inhibitors for the treatment of schizophrenia
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A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D2 ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D2 partial agonists and serotonin reuptake inhibitors. Structure-activity studies revealed that the linker plays a key role in contributing to D2 affinity, function, and SRI activity.
- Yan, Yinfa,Zhou, Ping,Rotella, David P.,Feenstra, Rolf,Kruse, Chris G.,Reinders, Jan-Hendrik,Neut, Martina van der,Lai, Margaret,Zhang, Jean,Kowal, Dianne M.,Carrick, Tikva,Marquis, Karen L.,Pausch, Mark H.,Robichaud, Albert J.
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scheme or table
p. 2983 - 2986
(2010/08/06)
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- Synthesis, in vitro characterization, and radiolabeling of N,N-dimethyl-2-(2′-amino-4′-substituted-phenylthio)benzylamines: Potential candidates as selective serotonin transporter radioligands
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A series of N,N-dimethylated and N-monomethylated analogues of N,N-dimethyl-2-(2′-amino-4′-iodophenylthio)benzylamine substituted at the 4′-phenyl position have been prepared and evaluated in vitro for serotonin transporter (SERT) selectivity. Several der
- Jarkas, Nachwa,McConathy, Jonathan,Voll, Ronald J.,Goodman, Mark M.
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p. 4254 - 4265
(2007/10/03)
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