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.

一项高通量筛选 (HTS) 活动确定了一种全新的 mGlu ₇ NAM 化学型，该化学型基于 8-甲氧基-4-(4-苯基哌嗪-1-基)喹诺酮羧酸酯核心。初始命中 VU0226390 是一种有效的 mGlu ₇ NAM（IC ₅₀  = 647 nM，6% L-AP4 min），与其他 III 组 mGlu 受体相比具有选择性（相对于 mGlu ₄和 mGlu ₈ >30 μM ）。多维优化工作调查了这种新化学型的所有区域，发现了非常陡峭的 SAR，让人想起变构调节剂和意想不到的哌嗪模拟物（而经典生物电子等排体失败了）。虽然 mGlu ₇ NAM 效力可以提高（IC ₅₀ s ~ 350 nM），但乙酯部分的必要性以及较差的理化和 DMPK 特性阻碍了对体内工具化合物或临床候选物的优化。尽管如此，这场从热门到领先的活动提供了关键的药物化学见解和新机遇。