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SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M PAMs


AUTHORS

Chopko TCTrevor C , Han CChangho , Gregro ARAlison R , Engers DWDarren W , Felts ASAndrew S , Poslusney MSMike S , Bollinger KAKatrina A , Morrison RDRyan D , Bubser MMichael , Lamsal AAtin , Luscombe VBVincent B , Cho HPHyekyung P , Schnetz-Boutaud NCNathalie C , Rodriguez ALAlice L , Chang SSichen , Daniels JSJ Scott , Stec DFDonald F , Niswender CMColleen M , Jones CKCarrie K , Wood MRMichael R , Wood MWMichael W , Duggan MEMark E , Brandon NJNicholas J , Conn PJP Jeffrey , Bridges TMThomas M , Lindsley CWCraig W , Melancon BJBruce J . Bioorganic & medicinal chemistry letters. 2019 6 20; 29(16). 2224-2228

ABSTRACT

This letter describes progress towards an M PAM 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 M PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.



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