- NOVEL COMPOUNDS
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The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase L1 (UCHL1). The invention further relates to the use of DUB inhibitors in the treatment of cancer and other indications. Compounds of the invention include compounds having the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 to R8 are as defined herein.
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Page/Page column 133-134
(2016/04/20)
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- 1-Aryl-4-nitro-1H-imidazoles, a new promising series for the treatment of human African trypanosomiasis
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Nitroimidazoles are a well-known class of antibacterial and antiprotozoal drugs but in spite of the widespread clinical and veterinary use of these drugs, this family has been stigmatized in part due to associated genotoxicity problems. Here we report the synthesis, the anti-trypanosomal activity and a structure-activity relationship (SAR) study of a series of about fifty 1-aryl-4-nitro-1H-imidazoles, with an emphasis on selected in vivo active molecules. Compounds 4-nitro-1-{4-(trifluoromethoxy)phenyl}-1H-imidazole and 1-(3,4-dichlorophenyl)-4-nitro-1H-imidazole are curative in mouse models of both acute and chronic African trypanosomiasis when given orally at doses of 25-50 mg/kg for 4 days for the acute infection, and 50-100 mg/kg (bid) for 5 days in the chronic model. While both compounds are bacterial mutagens, activity is lost in strains lacking bacterial specific nitro-reductases. Mammalian nitro-reductases do not reduce nitroaromatic compounds with low redox potentials with same avidity as their bacterial counterparts and these compounds were shown to be devoid of genotoxicity in mammalian cells. Both compounds are promising leads for the treatment of human African trypanosomiasis (HAT or sleeping sickness), including the fatal stage 2 of the disease, for which new treatments are urgently needed.
- Trunz, Bernadette Bourdin,Jdrysiak, Rafa?,Tweats, David,Brun, Reto,Kaiser, Marcel,Suwiński, Jerzy,Torreele, Els
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experimental part
p. 1524 - 1535
(2011/05/06)
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- Novel orally active NPY Y5 receptor antagonists: Synthesis and structure-activity relationship of spiroindoline class compounds
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Spiroindoline urea derivatives, designed to act as NPY Y5 receptor antagonists, were synthesized and their structure-activity relationships were investigated. Of these derivatives, compound 3a showed good Y5 binding affinity with favorable pharmacokinetic
- Sakamoto, Toshihiro,Moriya, Minoru,Tsuge, Hiroyasu,Takahashi, Toshiyuki,Haga, Yuji,Nonoshita, Katsumasa,Okamoto, Osamu,Takahashi, Hirobumi,Sakuraba, Aya,Hirohashi, Tomoko,Shibata, Takunobu,Kanno, Tetsuya,Ito, Junko,Iwaasa, Hisashi,Gomori, Akira,Ishihara, Akane,Fukuroda, Takahiro,Kanatani, Akio,Fukami, Takehiro
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experimental part
p. 5015 - 5026
(2009/12/04)
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- Synthesis and characterization of some 1-halophenyl-4-nitroimidazoles
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Several 1-(chloro, fluoro, dichloro or difluorophenyl)-4-nitroimidazoles and their 2-methy 1 derivatives have been prepared by the reaction of respectively substituted anilines with 1,4-dinitroimidazoles via a degenerated imidazole ring transformation. Th
- Jedrysiak,Suwinski
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p. 1935 - 1948
(2008/09/18)
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