Cook James, Zusi F Christopher, McDonald Ivar M, King Dalton, Hill Matthew D, Iwuagwu Christiana, Mate Robert A, Fang Haiquan, Zhao Rulin, Wang Bei, Cutrone Jingfang, Ma Baoqing, Gao Qi, Knox Ronald J, Matchett Michele, Gallagher Lizbeth, Ferrante Meredith, Post-Munson Debra, Molski Thaddeus, Easton Amy, Miller Regina, Jones Kelli, Digavalli Siva, Healy Francine, Lentz Kimberley, Benitex Yulia, Clarke Wendy, Natale Joanne, Siuciak Judith A, Lodge Nicholas, Zaczek Robert, Denton Rex, Morgan Daniel, Bristow Linda J, Macor John E, Olson Richard E
Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
J Med Chem. 2016 Dec 22;59(24):11171-11181. doi: 10.1021/acs.jmedchem.6b01506. Epub 2016 Dec 13.
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-HT receptor. 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.
本文描述了一系列含奎宁环的螺恶唑烷（“螺亚胺酸酯”）的设计与合成，以及它们作为α7烟碱型乙酰胆碱受体部分激动剂的用途。该系列中的某些成员对α7受体表现出相对于高度同源的5-羟色胺受体的优异选择性。对N-螺亚胺酸酯杂环取代基的修饰得到了（1S,2R,4S）-N-异喹啉-3-基）-4'H-4-氮杂螺[双环[2.2.2]辛烷-2,5'-恶唑]-2'-胺（BMS-902483），一种有效的α7部分激动剂，其在临床前啮齿动物模型中改善了认知能力。
