- Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure–Activity Relationships, and Sleep-Promoting Properties in Rats
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The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone (3), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone (51), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats.
- Brotschi, Christine,Roch, Catherine,Gatfield, John,Treiber, Alexander,Williams, Jodi T.,Sifferlen, Thierry,Heidmann, Bibia,Jenck, Francois,Bolli, Martin H.,Boss, Christoph
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supporting information
p. 1257 - 1270
(2019/06/17)
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- Oxadiazole pyrazole compound and application thereof
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The invention provides an oxadiazole pyrazole compound. The structure of the oxadiazole pyrazole compound is as shown in Formula I. The compound has an insecticidal action and can serve as an insecticide for preventing and controlling plant insect pests o
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Paragraph 0024; 0025; 0026
(2018/09/08)
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- Phthalate oxethyl oxadiazole linked parazole compound and application thereof
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The invention provides a phthalate oxethyl oxadiazole linked parazole compound. The structure of the compound is shown as a formula I (shown in the description). The compound of the formula I has a function of killing nematode, and can be used as a nemato
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Paragraph 0021; 0022; 0023; 0024
(2019/01/07)
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- Design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5
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Cyclic nucleotide phosphodiesterase type 5 (PDE5) is a prime drug target for treating the diseases associated with a lower level of the cyclic guanosine monophosphate (cGMP), which is a specific substrate for PDE5 hydrolysis. Here we report a series of novel PDE5 inhibitors with the new scaffold of the monocyclic pyrimidin-4(3H)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4(3H)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDE5, resulting in 25 compounds with IC50 ranging from 1 to 100 nM and 11 compounds with IC50 ranging from 1 to 10 nM. Compound 5, 5,6-diethyl-2-[2-n-propoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl] pyrimid-4(3H)-one, the most potent compound, has an excellent IC50 (1.6 nM) in vitro and a good efficacy in a rat model of erection. It thus provides a potential candidate for the further development into a new drug targeting PDE5.
- Wang, Guan,Liu, Zheng,Chen, Tiantian,Wang, Zhen,Yang, Huaiyu,Zheng, Mingyue,Ren, Jing,Tian, Guanghui,Yang, Xiaojun,Li, Li,Li, Jianfeng,Suo, Jin,Zhang, Rongxia,Jiang, Xiangrui,Terrett, Nicholas Kenneth,Shen, Jingshan,Xu, Yechun,Jiang, Hualiang
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p. 10540 - 10550
(2013/02/22)
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- OXADIAZOLE DIARYL COMPOUNDS
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The invention relates to compounds of formula (I): wherein R1, R2, Ra , Rb,Rc and W, have the meanings given in claim 1. The compounds are useful e.g. in the treatment of autoimmune disorders, such as multiple sclerosis.
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Page/Page column 54
(2009/05/29)
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- Process for the preparation of sulphonamide-substituted imidazotriazinones
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The present invention relates to a process for the preparation of sulphonamide-substituted imidazotriazinones of the general formula (I) characterized in that compounds of the formula (II) are reacted with sulphuric acid and the products obtained are then reacted with thionyl chloride and converted in situ in an inert solvent using an amine into the compounds according to the invention and, if appropriate, reacted to give the corresponding salts, hydrates or N-oxides.
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