Selecting a known HTS hit with the pyrazolo[1,5-a]pyrimidine core, our project was started from CMPPE, and its optimization was driven by a ligand-based pharmacophore model developed on the basis of published GABA_B positive allosteric modulators (PAMs). Our primary goal was to improve the potency by finding new enthalpic interactions. Therefore, we included the lipophilic ligand efficiency (LLE or LipE) as an objective function in the optimization that led to a carboxylic acid derivative (34). This lead candidate offers the possibility to improve potency without drastically inflating the physicochemical properties. Although the discovery of the novel carboxyl feature was surprising, it turned out to be an important element of the GABA_B PAM pharmacophore that can be perfectly explained based on the new protein structures. Rationalizing the binding mode of 34, we analyzed the intersubunit PAM binding site of GABA_B receptor using the publicly available experimental structures.

中文翻译：

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新型 GABAB PAM：从蛋白质结构看构效关系

选择具有吡唑并[1,5- a ]嘧啶核心的已知HTS命中，我们的项目从CMPPE开始，其优化是由基于已发表的GABA _B正变构调节剂（PAMs）开发的基于配体的药效团模型驱动的）。我们的主要目标是通过寻找新的焓相互作用来提高效力。因此，我们将亲脂性配体效率（LLE 或 LipE）作为优化的目标函数，从而产生了羧酸衍生物 ( 34 )。该主要候选药物提供了在不大幅提高理化特性的情况下提高效力的可能性。尽管新的羧基特征的发现令人惊讶，但事实证明它是 GABA _B PAM 药效团的重要元素，可以根据新的蛋白质结构完美地解释。为了合理化34的结合模式，我们使用公开的实验结构分析了 GABA _{B受体的亚基间 PAM 结合位点。}