title: Development of 4-Heteroarylamino-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octanes] as α7 Nicotinic Receptor Agonists.
abstract: We describe the synthesis of quinuclidine-containing spiroimidates and their utility as α7 nicotinic acetylcholine receptor (nAChR) partial agonists. A convergent synthetic route allowed for rapid SAR investigation and provided a diverse set of fused 6,5-heteroaryl analogs. Two potent and selective α7 nAChR partial agonists, (1'S,3'R,4'S)-N-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine (20) and (1'S,3'R,4'S)-N-(7-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine (21), were identified. Both agonists improved cognition in a preclinical rodent model of learning and memory. Additionally, 5-HT3Areceptor SAR suggested the presence of a steric site that when engaged led to significant loss of affinity at that receptor.
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hill
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Haiquan
authors.initials: H
authors.lastname: Fang
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: H Dalton
authors.initials: HD
authors.lastname: King
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Christiana I
authors.initials: CI
authors.lastname: Iwuagwu
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Ivar M
authors.initials: IM
authors.lastname: McDonald
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: James
authors.initials: J
authors.lastname: Cook
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: F Christopher
authors.initials: FC
authors.lastname: Zusi
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mate
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Knox
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Debra
authors.initials: D
authors.lastname: Post-Munson
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Easton
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Regina
authors.initials: R
authors.lastname: Miller
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Lentz
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Wendy
authors.initials: W
authors.lastname: Clarke
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Benitex
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lodge
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Rex
authors.initials: R
authors.lastname: Denton
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Bristow
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Olson
keywords: novel object recognition; quinuclidine; schizophrenia; α7 nAChR