title: Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4).
abstract: The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu4) in preclinical rodent models of Parkinson's disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu4 PAM, N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506). We detail the discovery of VU0418506 starting from a common picolinamide core scaffold and evaluation of a number of amide bioisosteres leading to the novel pyrazolo[4,3-b]pyridine head group. VU0418506 has been characterized as a potent and selective mGlu4 PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species.
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.forename: Rocco D
authors.initials: RD
authors.lastname: Gogliotti
authors.forename: Yiu-Yin
authors.initials: YY
authors.lastname: Cheung
authors.forename: James M
authors.initials: JM
authors.lastname: Salovich
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Garcia-Barrantes
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Ryan
authors.initials: R
authors.lastname: Morrison
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Soars
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Zhuo
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hurley
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D018683:Excitatory Amino Acid Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010848:Picolinic Acids / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D018683:Excitatory Amino Acid Agents; D010848:Picolinic Acids; D011720:Pyrazoles; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; C000624246:Vu0418506; C003142:picolinamide; C023666:pyridine; C108823:metabotropic glutamate receptor 4
keywords: CYP induction; Metabotropic glutamate receptor 4; Parkinson’s disease; mGlu4; pyrazolo[4,3-b]pyridine