Spinal muscular atrophy (SMA) is a neurodegenerative disorder that results from mutations in the SMN1 gene, leading to survival motor neuron (SMN) protein deficiency. One therapeutic strategy for SMA is to identify compounds that enhance the expression of the SMN2 gene, which normally only is a minor contributor to functional SMN protein production, but which is unaffected in SMA. A recent high-throughput screening campaign identified a 3,4-dihydro-4-phenyl-2(1H)-quinolinone derivative (2) that increases the expression of SMN2 by 2-fold with an EC₅₀ = 8.3 µM. A structure-activity relationship (SAR) study revealed that the array of tolerated substituents, on either the benzo portion of the quinolinone or the 4-phenyl, was very narrow. However, the lactam ring of the quinolinone was more amenable to modifications. For example, the quinazolinone (9a) and the benzoxazepin-2(3H)-one (19) demonstrated improved potency and efficacy for increase in SMN2 expression as compared to 2.

脊髓性肌萎缩症 (SMA) 是一种神经退行性疾病，由SMN1基因突变导致，导致运动神经元存活 (SMN) 蛋白缺乏。SMA 的一种治疗策略是识别增强SMN2基因表达的化合物，该基因通常对功能性 SMN 蛋白的产生仅起很小的作用，但在 SMA 中不受影响。最近的一项高通量筛选活动发现了一种 3,4-二氢-4-苯基-2(1H)-喹啉酮衍生物 ( 2 )，它可以将SMN2的表达增加2 倍，EC ₅₀  = 8.3 µM。构效关系 (SAR) 研究表明，喹啉酮的苯并部分或 4-苯基上的可耐受取代基的范围非常窄。然而，喹啉酮的内酰胺环更易于修饰。例如，与2相比，喹唑啉酮( 9a )和苯并恶西平-2(3H)-酮( 19 )在增加SMN2表达方面表现出更好的效力和功效。