- 5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms
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Trypanothione synthetase is an essential enzyme for kinetoplastid parasites which cause highly disabling and fatal diseases in humans and animals. Inspired by the observation that N(5)-substituted paullones inhibit the trypanothione synthetase from the related parasite Leishmania infantum, we designed and synthesized a series of new derivatives. Although none of the new compounds displayed strong inhibition of Trypanosoma brucei trypanothione synthetase, several of them caused a remarkable growth inhibition of cultivated Trypanosoma brucei bloodstream forms. The most potent congener 3a showed antitrypanosomal activity in double digit nanomolar concentrations and a selectivity index of three orders of magnitude versus murine macrophage cells.
- Orban, Oliver C.F.,Korn, Ricarda S.,Benítez, Diego,Medeiros, Andrea,Preu, Lutz,Loa?c, Nadège,Meijer, Laurent,Koch, Oliver,Comini, Marcelo A.,Kunick, Conrad
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Read Online
- Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of polo-like kinase 1 (MLN0905)
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This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.
- Duffey, Matthew O.,Vos, Tricia J.,Adams, Ruth,Alley, Jennifer,Anthony, Justin,Barrett, Cynthia,Bharathan, Indu,Bowman, Douglas,Bump, Nancy J.,Chau, Ryan,Cullis, Courtney,Driscoll, Denise L.,Elder, Amy,Forsyth, Nancy,Frazer, Jonathan,Guo, Jianping,Guo, Luyi,Hyer, Marc L.,Janowick, David,Kulkarni, Bheemashankar,Lai, Su-Jen,Lasky, Kerri,Li, Gang,Li, Jing,Liao, Debra,Little, Jeremy,Peng, Bo,Qian, Mark G.,Reynolds, Dominic J.,Rezaei, Mansoureh,Scott, Margaret Porter,Sells, Todd B.,Shinde, Vaishali,Shi, Qiuju Judy,Sintchak, Michael D.,Soucy, Francois,Sprott, Kevin T.,Stroud, Stephen G.,Nestor, Michelle,Visiers, Irache,Weatherhead, Gabriel,Ye, Yingchun,Damore, Natalie
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supporting information; experimental part
p. 197 - 208
(2012/03/10)
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- LACTAM COMPOUNDS USEFUL AS PROTEIN KINASE INHIBITORS
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The present invention provides novel compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.
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Page/Page column 311
(2008/06/13)
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- Synthesis of 7-phenylpyrimido[5,4-d][1]benzazepin-2-ones
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The syntheses of the 7-phenylpyrimido[5,4-d][1]benzazepin-2-ones 3, 4, and 5 are described. The 7-phenyl group was introduced by phenylation of the lactam nitrogen in 10, 13 and 16 respectively. One of these compounds, 5, showed moderate activity as a CNS agent.
- Chen,Gilman
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p. 663 - 666
(2007/10/02)
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