Discovery and characterization of AZD9272 and AZD6538—Two novel mGluR5 negative allosteric modulators selected for clinical development

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Abstract

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.

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Acknowledgments

The authors are grateful to Pam Jacobson and the core tissue culture group at NPS Salt Lake City for their contribution to developing the cell lines, to Julie Grabell and Josee Normand (NPS Toronto) for their technical assistance in developing and implementing binding studies and IP assay, to Brad VanWagenen (NPS SLC) for his contribution to chemistry and to the late Allan Johnson (AstraZeneca) who designed and performed the autoradiographic studies.

We also want to thank Edwin Johnson

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