Skip to main content

Niswender Laboratory

Synthesis and SAR of a series of mGlu NAMs based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinoline carboxylate core

AUTHORS

Kalbfleisch JJJacob J , Reed CWCarson W , Park CCharlotte , Spearing PKPaul K , Quitalig MCMarc C , Jenkins MTMatthew T , Rodriguez ALAlice L , Blobaum ALAnna L , Conn PJP Jeffrey , Niswender CMColleen M , Lindsley CWCraig W . Bioorganic & medicinal chemistry letters. 2020 9 2; 30(22). 127529

ABSTRACT

A High-Throughput Screening (HTS) campaign identified a fundamentally new mGlu NAM chemotype, based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinolone carboxylate core. The initial hit, VU0226390, was a potent mGlu NAM (IC = 647 nM, 6% L-AP4 min) with selectivity versus the other group III mGlu receptors (>30 μM vs. mGlu and mGlu). A multi-dimensional optimization effort surveyed all regions of this new chemotype, and found very steep SAR, reminiscent of allosteric modulators, and unexpected piperazine mimetics (whereas classical bioisosteres failed). While mGlu NAM potency could be improved (ICs ~ 350 nM), the necessity of the ethyl ester moiety and poor physiochemical and DMPK properties precluded optimization towards in vivo tool compounds or clinical candidates. Still, this hit-to-lead campaign afforded key medicinal chemistry insights and new opportunities.

Tags: