title: Triazolopyridine ethers as potent, orally active mGlu2positive allosteric modulators for treating schizophrenia.
abstract: Triazolopyridine ethers with mGlu2positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2PAMs for the treatment of schizophrenia and merit further preclinical investigation.
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA. Electronic address: mendi.higgins@bms.com.
authors.forename: Mendi A
authors.initials: MA
authors.lastname: Higgins
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Marcin
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: F
authors.initials: F
authors.lastname: Christopher Zusi
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Gentles
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Ding
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Pearce
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Easton
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Kostich
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Seager
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Bourin
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bristow
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Johnson
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Miller
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hogan
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Whiterock
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gulianello
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Ferrante
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Hendricson
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Alt
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004987:Ethers / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000882:Haplorhini; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004987:Ethers; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D014230:Triazoles; C108822:metabotropic glutamate receptor 2
keywords: Metabotropic glutamate receptors; Schizophrenia; Triazolopyridine; mGlu(2)