Spinal Muscular Atrophy (SMA) is a neurodegenerative disease that is the leading cause of infant mortality worldwide. SMA results from low levels of survival motor neuron (SMN) protein due to a mutation or deletion of the SMN1 gene. The SMN2 gene does not produce sufficient amounts of SMN protein to prevent SMA. In an effort to identify compounds that target the SMN2 gene during transcription or stabilize the SMN protein, a large library of small molecules was tested in an SMN2-luciferase assay. As a result, a 3,4-dihydro-4-phenyl-2(1H)-quinolinone derivative (EC50 = 8.3 μM) was identified as a hit compound that increased SMN protein in vitro and in vivo. A structure-analysis relationship (SAR) study was started to improve the activity of the hit compound. The most active analog from the SAR study (LDN-2391, EC50 = 4.1 μM) was racemic. Both enantiomers of LDN-2391 were separated by chiral column chromatography. One of the enantiomers (LDN-4301, EC50 = 1.4 μM) held all of the activity in the SMN2-lucerifarase assay, and the other enantiomer (LDN-4300) was inactive. The stereocenter of LDN-4301 was R, and this was determined via x-ray crystallography. The SAR study, to improve the activity and solubility of the new analogs, is in progress and will be reported here.

Small molecule quinolinone derivatives that increase survival motor neuron protein via an SMN2 gene transcription enhancing mechanism

256th National Meeting (2018)

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