Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers

Abstract 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 EC 50  = 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 .