title: Design and Synthesis of a New Series of 4-Heteroarylamino-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octanes as α7 Nicotinic Receptor Agonists. 1. Development of Pharmacophore and Early Structure-Activity Relationship.
abstract: The design and synthesis of a series of quinuclidine-containing spirooxazolidines ("spiroimidates") and their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for α7 over the highly homologous 5-HT3Areceptor. Modification of the N-spiroimidate heterocycle substituent led to (1S,2R,4S)-N-isoquinolin-3-yl)-4'H-4-azaspiro[bicyclo[2.2.2]octane-2,5'oxazol]-2'-amine (BMS-902483), a potent α7 partial agonist, which improved cognition in preclinical rodent models.
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: James
authors.identifier: 0000-0002-1948-4039
authors.initials: J
authors.lastname: Cook
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: F Christopher
authors.initials: FC
authors.lastname: Zusi
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Ivar M
authors.initials: IM
authors.lastname: McDonald
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Dalton
authors.initials: D
authors.lastname: King
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hill
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Christiana
authors.initials: C
authors.lastname: Iwuagwu
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mate
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Haiquan
authors.initials: H
authors.lastname: Fang
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Rulin
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Jingfang
authors.initials: J
authors.lastname: Cutrone
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Baoqing
authors.initials: B
authors.lastname: Ma
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Knox
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Matchett
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Gallagher
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Meredith
authors.initials: M
authors.lastname: Ferrante
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Debra
authors.initials: D
authors.lastname: Post-Munson
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Molski
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Easton
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Regina
authors.initials: R
authors.lastname: Miller
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Kelli
authors.initials: K
authors.lastname: Jones
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Siva
authors.initials: S
authors.lastname: Digavalli
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Francine
authors.initials: F
authors.lastname: Healy
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Lentz
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Benitex
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Wendy
authors.initials: W
authors.lastname: Clarke
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Joanne
authors.initials: J
authors.lastname: Natale
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Siuciak
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lodge
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Rex
authors.initials: R
authors.lastname: Denton
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bristow
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
mesh_terms: D000818:Animals; D034242:Cyclooctanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors*
chemical_list: D034242:Cyclooctanes; D018722:Nicotinic Agonists; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor