化学
亲脂性
选择性
立体化学
对映体
钙通道
电压依赖性钙通道
蛋白质亚单位
钙
组合化学
生物化学
有机化学
基因
催化作用
作者
Ariadna Fernández,José Luis Dı́az,Monica A. Garcia,Sergi Rodríguez-Escrich,Adriana Lorente,Raquel Enrech,Alberto Dordal,Enrique Portillo‐Salido,Mónica Porras,Begoña Fernández,Raquel F. Reinoso,José Miguel Vela,Carmen Almansa
标识
DOI:10.1021/acsmedchemlett.1c00416
摘要
The synthesis and pharmacological activities of a new series of piperazinyl quinazolin-4-(3H)-one derivatives acting toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) are reported. Different positions of a micromolar HTS hit were explored, and best activities were obtained for compounds containing a small alkyl group in position 3 of the quinazolin-4-(3H)-one scaffold and a 3-methyl-piperazin-1-yl- or 3,5-dimethyl-piperazin-1-yl-butyl group in position 2. The activity was shown to reside in the R enantiomer of the chain in position 2, and several eutomers reached single digit nanomolar affinities. Final modification of the central scaffold to reduce lipophilicity provided the pyrido[4,3-d]pyrimidin-4(3H)-one 16RR, which showed high selectivity for Cavα2δ-1 versus Cavα2δ-2, probably linked to its improved analgesic efficacy-safety ratio in mice over pregabalin.
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