Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyrazine (PF470): a highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator.

@article{Zhang2014DiscoveryAP,
  title={Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyrazine (PF470): a highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator.},
  author={Lei Zhang and Gayatri Balan and Gabriela Barreiro and Brian P Boscoe and Lois K Chenard and Julie A Cianfrogna and Michelle M. Claffey and Laigao Chen and Karen J Coffman and Susan E Drozda and Joshua R Dunetz and Kari R. Fonseca and Paul Galatsis and Sarah Grimwood and John T. Lazzaro and Jessica Y Mancuso and Emily L Miller and Matthew R Reese and Bruce N. Rogers and Isao Sakurada and Marc B. Skaddan and Deborah Lea Smith and Antonia F Stepan and Patrick E. Trapa and Jamison B Tuttle and Patrick R. Verhoest and Daniel P Walker and Ann S. Wright and Margaret M. Zaleska and Kenneth Zasadny and Christopher L. Shaffer},
  journal={Journal of medicinal chemistry},
  year={2014},
  volume={57 3},
  pages={861-77}
}
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) as a highly potent… CONTINUE READING