Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
Department of Molecular Engineering, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
Eur J Med Chem. 2017 Sep 8;137:63-75. doi: 10.1016/j.ejmech.2017.05.036. Epub 2017 May 12.
Glycine receptors (GlyRs) are pentameric glycine-gated chloride ion channels that are enriched in the brainstem and spinal cord where they have been demonstrated to play a role in central nervous system (CNS) inhibition. Herein we describe two novel classes of glycine receptor potentiators that have been developed using similarity- and property-guided scaffold hopping enabled by parallel synthesis and pharmacophore-based virtual screening strategies. This effort resulted in the identification of novel, efficient and modular leads having favorable in vitro ADME profiles and high CNS multi-parameter optimization (MPO) scores, exemplified by azetidine sulfonamide 19 and aminothiazole sulfone (ent2)-20.
甘氨酸受体（GlyRs）是五聚体甘氨酸门控氯离子通道，在脑桥和脊髓中丰富存在，在那里它们被证明在中枢神经系统（CNS）抑制中发挥作用。在此，我们描述了两类新型甘氨酸受体增强剂，它们是使用基于相似性和性质的支架跳跃以及平行合成和基于药效团的虚拟筛选策略开发的。这项工作导致了新型、高效和模块化先导化合物的鉴定，这些先导化合物具有有利的体外 ADME 特性和高 CNS 多参数优化（MPO）评分，以氮杂环丁烷磺酰胺 19 和氨基噻唑砜（ent2）-20 为例。
