title: 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.
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.
authors.affiliation: Neuroscience Medicinal Chemistry, ‡Neuroscience Pharmacokinetics, Dynamics and Metabolism, and §Neuroscience Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Gayatri
authors.initials: G
authors.lastname: Balan
authors.forename: Gabriela
authors.initials: G
authors.lastname: Barreiro
authors.forename: Brian P
authors.initials: BP
authors.lastname: Boscoe
authors.forename: Lois K
authors.initials: LK
authors.lastname: Chenard
authors.forename: Julie
authors.initials: J
authors.lastname: Cianfrogna
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Claffey
authors.forename: Laigao
authors.initials: L
authors.lastname: Chen
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Coffman
authors.forename: Susan E
authors.initials: SE
authors.lastname: Drozda
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Dunetz
authors.forename: Kari R
authors.initials: KR
authors.lastname: Fonseca
authors.forename: Paul
authors.initials: P
authors.lastname: Galatsis
authors.forename: Sarah
authors.initials: S
authors.lastname: Grimwood
authors.forename: John T
authors.initials: JT
authors.lastname: Lazzaro
authors.forename: Jessica Y
authors.initials: JY
authors.lastname: Mancuso
authors.forename: Emily L
authors.initials: EL
authors.lastname: Miller
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reese
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Rogers
authors.forename: Isao
authors.initials: I
authors.lastname: Sakurada
authors.forename: Marc
authors.initials: M
authors.lastname: Skaddan
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Smith
authors.forename: Antonia F
authors.initials: AF
authors.lastname: Stepan
authors.forename: Patrick
authors.initials: P
authors.lastname: Trapa
authors.forename: Jamison B
authors.initials: JB
authors.lastname: Tuttle
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Walker
authors.forename: Ann S
authors.initials: AS
authors.lastname: Wright
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Zaleska
authors.forename: Kenneth
authors.initials: K
authors.lastname: Zasadny
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Shaffer
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D001682:Biological Availability; D002463:Cell Membrane Permeability; D004285:Dogs; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy; D057809:HEK293 Cells; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced; D007980:Levodopa / Q000009:adverse effects; D008252:Macaca fascicularis; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C587726:1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo(3,4-b)pyrazine; D000978:Antiparkinson Agents; D011719:Pyrazines; D011720:Pyrazoles; D064529:Receptor, Metabotropic Glutamate 5; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine