1620514-68-2Relevant academic research and scientific papers
Use of Intramolecular 1,5-Sulfur-Oxygen and 1,5-Sulfur-Halogen Interactions in the Design of N-Methyl-5-aryl- N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine SMN2 Splicing Modulators
Axford, Jake,Sung, Moo Je,Manchester, John,Chin, Donovan,Jain, Monish,Shin, Youngah,Dix, Ina,Hamann, Lawrence G.,Cheung, Atwood K.,Sivasankaran, Rajeev,Briner, Karin,Dales, Natalie A.,Hurley, Brian
, p. 4744 - 4761 (2021/05/07)
Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from a deletion or loss of function mutation of the survival motor neuron 1 (SMN1) gene. Branaplam (1) elevates levels of full-length SMN protein in vivo by modulating the splicing of the related gene SMN2 to enhance the exon-7 inclusion and increase levels of the SMN. The intramolecular hydrogen bond present in the 2-hydroxyphenyl pyridazine core of 1 enforces a planar conformation of the biaryl system and is critical for the compound activity. Scaffold morphing revealed that the pyridazine could be replaced by a 1,3,4-thiadiazole, which provided additional opportunities for a conformational constraint of the biaryl through intramolecular 1,5-sulfur-oxygen (S···O) or 1,5-sulfur-halogen (S···X) noncovalent interactions. Compound 26, which incorporates a 2-fluorophenyl thiadiazole motif, demonstrated a greater than 50% increase in production of full-length SMN protein in a mouse model of SMA.
THIADIAZOLE ANALOGS THEREOF AND METHODS FOR TREATING SMN-DEFICIENCY-RELATED-CONDITIONS
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Paragraph 0391; 0392, (2014/08/06)
The present invention provides a compound of Formula (X) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacolo
