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

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

doi:10.1021/jm401622k

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

J Med Chem. 2014 Feb 13;57(3):861-77. doi: 10.1021/jm401622k. Epub 2014 Jan 22.

Affiliation

¹ Neuroscience Medicinal Chemistry, ‡Neuroscience Pharmacokinetics, Dynamics and Metabolism, and §Neuroscience Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.

PMID: 24392688
DOI: 10.1021/jm401622k

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.

MeSH terms

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Administration, Oral
Allosteric Regulation
Animals
Antiparkinson Agents / adverse effects
Biological Availability
Cell Membrane Permeability
Dogs
Dyskinesia, Drug-Induced / drug therapy
HEK293 Cells
Humans
Hypersensitivity, Delayed / chemically induced
Levodopa / adverse effects
Macaca fascicularis
Madin Darby Canine Kidney Cells
Male
Microsomes, Liver / metabolism
Models, Molecular
Parkinson Disease / drug therapy
Parkinson Disease / etiology
Parkinson Disease / physiopathology
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*
Structure-Activity Relationship

Substances

1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo(3,4-b)pyrazine
Antiparkinson Agents
Pyrazines
Pyrazoles
Receptor, Metabotropic Glutamate 5
Levodopa
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine