Discovery and characterization of AZD9272 and AZD6538¡ªTwo novel mGluR5 negative allosteric modulators selected for clinical development
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- 作者：Patrick Raboisson ; Anna Breitholtz-Emanuelsson ; Henrik Dahll?f ; Louise Edwards ; William L. Heaton ; Methvin Isaac ; Keith Jarvie ; Annika Kers ; Alex ; er B.E. Minidis ; Anna Nordmark ; Susan M. Sheehan ; Abdelmalik Slassi ; Peter Str?m ; Ylva Terelius ; David Wensbo ; Julie M. Wilson ; Tao Xin ; Donald A. McLeod
- 关键词：mGluR5 ; Negative allosteric modulator ; GPCR ; In vitro pharmacology ; Pain ; Clinical candidate
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：15 November, 2012
- 年：2012
- 卷：22
- 期：22
- 页码：6974-6979
- 全文大小：1537 K
文摘
AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.