Synthesis of mono-fluoromethyl 6,5-heteroaromatic bicycles using 1,3-difluoroacetone as a cyclising reagent

The development of facile, wide scope synthetic methodologies providing access to fluorinated motifs is important in medic-inal chemistry; for our purposes, we are interested in developing fluorine-tagged compounds to investigate their utility in Huntington’s disease. Here, we describe a novel, operationally simple and mild procedure for the synthesis of mono-fluoromethyl 6,5-heteroaromatic bicycles using 1,3-difluoroacetone (DFA). The scope of the reaction was investigated, and 27 examples synthesized with yields up to 96%

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington’s Disease

Huntington’s disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam