- Design and optimization of purine derivatives as in vivo active PDE10A inhibitors
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Phosphodiesterases are important enzymes regulating signal transduction mediated by second messenger molecules cAMP or cGMP. PDE10A is a unique member in the PDE family because of its selective expression in medium spiny neurons. It is recognized as anti-psychotic drug target. Based on the structural similarity between our previous chemistry work on 8-aminoimidazo[1,2-a]pyrazines and the PDE10A inhibitors reported by Bartolome-Nebreda et al., we initialized a project for developing PDE10A inhibitors. After several rounds of optimization, we were able to obtain a few compounds with good PDE10A enzymatic activity. And after further PDE enzymatic selectivity study, metabolic stability assay and in vivo pharmacological tests we identified two inhibitors as interesting lead compounds with the potential for further PDE10A lead optimizatioin.
- Chen, Liu,Chen, Danqi,Tang, Le,Ren, Jing,Chen, Jiaojiao,Zhen, Xuechu,Liu, Yu-Chih,Zhang, Chenhua,Luo, Haibin,Shen, Jingkang,Xiong, Bing
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Read Online
- Formation of 1,3-diazocine by palladium catalyzed C-H arylation
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From multi-substituted 8-aminoimidazo[1,2-a]pyrazines, prepared via modified Groebke-Blackburn-Bienaymé reaction, a Pd-catalyzed cyclization reaction was discovered, leading to a rare (Z)-4,5-dihydro-3H-[1,3]diazocine system. Conditions of this cyclization were screened and DMF solvent was found as one of the key factors for the cyclization.
- Tang, Le,Ren, Jing,Ma, Yuchi,Wang, Xin,Chen, Lin,Shen, Jingkang,Chen, Yue-Lei,Xiong, Bing
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Read Online
- Discovery of a potent, selective, and orally active phosphodiesterase 10A inhibitor for the potential treatment of schizophrenia
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We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited select
- Bartolomé-Nebreda, José Manuel,Delgado, Francisca,Martín-Martín, María Luz,Martínez-Viturro, Carlos M.,Pastor, Joaquín,Tong, Han Min,Iturrino, Laura,Macdonald, Gregor J.,Sanderson, Wendy,Megens, Anton,Langlois, Xavier,Somers, Marijke,Vanhoof, Greet,Conde-Ceide, Susana
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p. 4196 - 4212
(2014/06/09)
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- PDE 10a Inhibitors for the Treatment of Type II Diabetes
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Disclosed are compounds, compositions and methods for treating Type II diabetes. Such compounds are represented by Formula (I) as follows: wherein R1, R2, L, and Q are defined herein.
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Paragraph 0438; 0441-0442
(2015/01/06)
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- Discovery and application of iminotriphenylphosphorane as a formal aromatic primary amine protecting group
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During our efforts to selectively synthesise N-arylated benzotriazole fragments, we developed a new primary aromatic amine protecting group strategy showing significant advantages over recognised protecting groups.
- Delouvrié, Bénédicte,Germain, Hervé,Harris, Craig S.,Lamorlette, Maryannick,Lebraud, Honorine,Nguyen, Ha Thi Hoang,Noisier, Anais,Ouvry, Gilles
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supporting information
p. 5380 - 5384
(2012/10/29)
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- IMIDAZO[1,2-a]PYRAZINE DERIVATIVES AND THEIR USE FOR THE PREVENTION OR TREATMENT OF NEUROLOGICAL, PSYCHIATRIC AND METABOLIC DISORDERS AND DISEASES
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The present invention relates to novel imidazo[1,2-a]pyrazine derivatives which are inhibitors of the phosphodiesterase 10 enzyme (PDE10) and which are useful for the treatment or prevention of neurological, psychiatric and metabolic disorders in which the PDE10 enzyme is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, to the use of such compounds or pharmaceutical compositions for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases.
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Page/Page column 33
(2013/02/28)
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- IMIDAZO [1, 2 -A] PYRAZINE DERIVATIVES AND THEIR USE FOR THE PREVENTION OR TREATMENT OF NEUROLOGICAL, PSYCHIATRIC AND METABOLIC DISORDERS AND DISEASES
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The present invention relates to novel imidazo[1,2-a]pyrazine derivatives which are inhibitors of the phosphodiesterase 10 enzyme (PDE10) and which are useful for the treatment or prevention of neurological, psychiatric and metabolic disorders in which the PDE10 enzyme is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, to the use of such compounds or pharmaceutical compositions for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases.
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Page/Page column 72
(2011/10/05)
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