Discovery of a Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitor for the Potential Treatment of Schizophrenia
详细信息 查看全文
- 作者：Jos茅 Manuel Bartolom茅-Nebreda ; Francisca Delgado ; Mar铆a Luz Mart铆n-Mart铆n ; Carlos M. Mart铆nez-Viturro ; Joaqu铆n Pastor ; Han Min Tong ; Laura Iturrino ; Gregor J. Macdonald ; Wendy Sanderson ; Anton Megens ; Xavier Langlois ; Marijke Somers ; Greet Vanhoof ; Susana Conde-Ceide
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：May 22, 2014
- 年：2014
- 卷：57
- 期：10
- 页码：4196-4212
- 全文大小：637K
- 年卷期：v.57,no.10(May 22, 2014)
- ISSN：1520-4804
文摘
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 selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure鈥揳ctivity and structure鈥損roperty relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.