SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M4 PAMs.
SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M4 PAMs.
复制标题
受醛氧化酶 (AO) 代谢启发的 SAR：新型中枢神经系统渗透性三环 M4 PAM 的发现。
DOI：
10.1016/j.bmcl.2019.06.032
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发表时间：
2019
影响因子：
2.7
通讯作者：
Rodriguez,Al
中科院分区：
文献类型：
--
作者：
Chopko,TrevorC;Han,Changho;Gregro,AlisonR;Engers,DarrenW;Felts,AndrewS;Poslusney,MikeS;Bollinger,KatrinaA;Morrison,RyanD;Bubser,Michael;Lamsal,Atin;Luscombe,VincentB;Cho,HyekyungP;Schnetz-Boutaud,NathalieC;Rodriguez,Al
This letter describes progress towards an M4PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M4PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robustin vivoefficacy in reversing amphetamine-induced hyperlocomotion in rats.
