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 M

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• 作者：Lei Zhang ; Gayatri Balan ; Gabriela Barreiro ; Brian P. Boscoe ; Lois K. Chenard ; Julie Cianfrogna ; Michelle M. Claffey ; Laigao Chen ; Karen J. Coffman ; Susan E. Drozda ; Joshua R. Dunetz ; Kari R. Fonseca ; Paul Galatsis ; Sarah Grimwood ; John T. Lazzaro ; Jessica Y. Mancuso ; Emily L. Miller ; Matthew R. Reese ; Bruce N. Rogers ; Isao Sakurada ; Marc Skaddan ; Deborah L. Smith ; Antonia F. Stepan ; Patrick Trapa ; Jamison B. Tuttle ; Patrick R. Verhoest ; Daniel P. Walker ; Ann S. Wright ; Margaret M. Zaleska ; Kenneth Zasadny ; Christopher L. Shaffer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：861-877
• 全文大小：699K
• ISSN：1520-4804

文摘

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鈥揳ctivity 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, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study.