Long, Madeline F., Engers, Julie L., Chang, Sichen, Zhan, Xiaoyan, Weiner, Rebecca L., Luscombe, Vincent B., Rodriguez, Alice L., Cho, Hyekyung P., Niswender, Colleen M., Bridges, Thomas M., Conn, P. Jeffrey, Engers, Darren W., and Lindsley, Craig W.
This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M 4 PAM activity in most M 4 PAMs to date, within the thieno[2,3- b ]pyridine core, as the β-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M 4 PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core. [ABSTRACT FROM AUTHOR]