Axford, Jake, Briner, Karin, Cheung, Atwood, Dales, Natalie, Hurley, Timothy, Jain, Monish, Sung, Moo, Manchester, John, Hamann, Lawrence, Chin, Donovan, Shin, Youngah and Sivasankaran, Rajeev (2021) 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. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

Abstract

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from 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 splicing of the related gene SMN2 to enhance exon-7 inclusion and increase levels of 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 compound activity. Scaffold morphing revealed that the pyridazine could be replaced by a 1,3,4-thiadiazole which provided additional opportunities for 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 fifty percent increase in production of full-length SMN protein in a mouse model of SMA.

Item Type:	Article
Date Deposited:	20 Apr 2021 00:45
Last Modified:	20 Apr 2021 00:45
URI:	https://oak.novartis.com/id/eprint/41745