| Literature DB >> 24392688 |
Lei Zhang1, 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.
Abstract
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.Entities:
Mesh：
Substances：
Year: 2014 PMID： 24392688 DOI： 10.1021/jm401622k
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446