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

• Published in: Journal of medicinal chemistry Vol. 57; no. 3; pp. 861 - 877
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.02.2014; Amer Chemical Soc
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Administration, Oral; Allosteric Regulation; Animals; Antiparkinson Agents - adverse effects; Biological Availability; Cell Membrane Permeability; Chemistry, Medicinal; Dogs; Dyskinesia, Drug-Induced - drug therapy; HEK293 Cells; Humans; Hypersensitivity, Delayed - chemically induced; Levodopa - adverse effects; Life Sciences & Biomedicine; Macaca fascicularis; Madin Darby Canine Kidney Cells; Male; Microsomes, Liver - metabolism; Models, Molecular; Parkinson Disease - drug therapy; Parkinson Disease - etiology; Parkinson Disease - physiopathology; Pharmacology & Pharmacy; Pyrazines - chemical synthesis; Pyrazines - pharmacology; Pyrazines - toxicity; Pyrazoles - chemical synthesis; Pyrazoles - pharmacology; Pyrazoles - toxicity; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5 - metabolism; Science & Technology; Structure-Activity Relationship; CENTRAL-NERVOUS-SYSTEM; DOPA-INDUCED DYSKINESIA; ANTAGONIST; ALIGNMENT; MONKEYS; EFFICIENCY
• ISSN: 0022-2623; 1520-4804
• 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.