Synthesis and SAR of a series of mGlu7 NAMs based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinoline carboxylate core.

Synthesis and SAR of a series of mGlu7 NAMs based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinoline carboxylate core.
Bioorg Med Chem Lett. 2020 Sep 02;:127529
Authors: Kalbfleisch JJ, Reed CW, Park C, Spearing PK, Quitalig MC, Jenkins MT, Rodriguez AL, Blobaum AL, Jeffrey Conn P, Niswender CM, Lindsley CW
Abstract
A High-Throughput Screening (HTS) campaign identified a fundamentally new mGlu7 NAM chemotype, based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinolone carboxylate core. The initial hit, VU0226390, was a potent mGlu7 NAM (IC50 = 647 nM, 6% L-AP4 min) with selectivity versus the other group III mGlu receptors (>30 μM vs. mGlu4 and mGlu8). 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 mGlu7 NAM potency could be improved (IC50s ∼ 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.
PMID: 32890686 [PubMed - as supplied by publisher]

Source: Bioorganic and Medicinal Chemistry Letters - September 1, 2020 Category: Chemistry Authors: Kalbfleisch JJ, Reed CW, Park C, Spearing PK, Quitalig MC, Jenkins MT, Rodriguez AL, Blobaum AL, Jeffrey Conn P, Niswender CM, Lindsley CW Tags: Bioorg Med Chem Lett Source Type: research