grn-529 and Parkinson-Disease

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.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Administration, Oral; Allosteric Regulation; Animals; Antiparkinson Agents; Biological Availability; Cell Membrane Permeability; Dogs; Dyskinesia, Drug-Induced; HEK293 Cells; Humans; Hypersensitivity, Delayed; Levodopa; Macaca fascicularis; Madin Darby Canine Kidney Cells; Male; Microsomes, Liver; Models, Molecular; Parkinson Disease; Pyrazines; Pyrazoles; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Structure-Activity Relationship