Herein, we describe the discovery of a potent, selective, brain-penetrating, in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To identify high-quality leads suitable for optimization and enable validation of the physiological function of PDE2A in vivo, structural modifications of the high-throughput screening hit 18 were performed. Our lead generation efforts revealed three key potency-enhancing functionalities with minimal increases in molecular weight (MW) and no change in topological polar surface area (TPSA). Combining these structural elements led to the identification of 6-methyl-N-((1R)-1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (38a), a molecule with the desired balance of preclinical properties. Further characterization by cocrystal structure analysis of 38a bound to PDE2A uncovered a unique binding mode and provided insights into its observed potency and PDE selectivity. Compound 38a significantly elevated 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brain following oral administration, thus validating this compound as a useful pharmacological tool and an attractive lead for future optimization.

中文翻译：

---

口服生物利用性，脑穿透性，体内活性磷酸二酯酶2A抑制剂铅系列的发现，用于治疗认知障碍

在本文中，我们描述了一种有效的，选择性的，可穿透脑的，体内活性磷酸二酯酶（PDE）2A抑制剂前导系列的发现。为了鉴定适合优化的高质量潜在客户并能够验证体内PDE2A的生理功能，对高通量筛选命中18进行了结构修饰。我们的潜在客户开发工作揭示了三个关键的效能增强功能，即分子量（MW）的增加最小，拓扑极性表面积（TPSA）不变。结合这些结构元素导致鉴定出6-甲基-N -（（（1 R）-1-（4-（三氟甲氧基）苯基）丙基）吡唑并[1,5- a ]嘧啶-3-羧酰胺（38a），具有临床前特性所需平衡的分子。通过与PDE2A结合的38a的共晶体结构分析进一步表征，揭示了独特的结合模式，并提供了对其所观察到的效价和PDE选择性的深入了解。口服后，化合物38a会显着提高小鼠大脑中3'，5'-环鸟苷单磷酸（cGMP）的水平，因此证实该化合物可作为有用的药理学工具和未来优化的引人注目的线索。