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

作者：Zhang Lei^*; Balan Gayatri; Barreiro Gabriela; Boscoe Brian P; Chenard Lois K; Cianfrogna Julie; Claffey Michelle M; Chen Laigao; Coffman Karen J; Drozda Susan E; Dunetz Joshua R; Fonseca Kari R; Galatsis Paul; Grimwood Sarah; Lazzaro John T; Mancuso Jessica Y; Miller Emily L; Reese Matthew R; Rogers Bruce N; Sakurada Isao; Skaddan Marc; Smith Deborah L; Stepan Antonia F; Trapa Patrick; Tuttle Jamison B; Verhoest Patrick R; Walker Daniel P

来源：Journal of Medicinal Chemistry, 2014, 57(3): 861-877.

DOI：10.1021/jm401622k

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, 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.

• 出版日期2014-2-13