Optimization of a series of isoxazoles for the treatment of spinal muscular atrophy

Abstract

Listen

Translate article

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder and the leading heritable cause of infant mortality. It is characterized by the degeneration of motor neurons within the anterior horn of the spinal cord resulting from low levels of survival motor neuron (SMN) protein. Often this occurs as a result of homozygous deletion of the telomeric SMN1 gene among patients, which codes for functional SMN protein. At least one copy of the centromeric SMN2 is found in all patients of SMA. This gene differs from SMN1 only in a single point mutation within exon 7 resulting in low levels of full-length SMN protein transcription at a level unable to compensate for the lack of SMN1 gene. Increasing functional SMN protein from SMN2 is currently a target for therapy as increasing the amount of SMN2 mRNA is believed to result in clinically significant disease treatment. No drug has been approved by the FDA for SMA and current therapies are lacking. To alleviate this, small molecule therapy has been a focus of the Laboratory for Drug Discovery in Neurodegeneration (LDDN) with an emphasis on increased SMN2 mRNA levels as well as stability of the SMN protein. An SAR study of one isoxazole scaffold, believed to stabilize the SMN protein, was performed to yield a library of small molecules. These compounds, reported herein, were designed to improve EC50, SMN2 availability, solubility, and plasma stability over the previous lead compound.