Details

Autor(en) / Beteiligte

• 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
• Wright, Ann S
• Zaleska, Margaret M
• Zasadny, Kenneth
• Shaffer, Christopher L

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2014-02, Vol.57 (3), p.861-877

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.