Inventors: Yv, H.; Liu-Bujalski, L.; Johnson, TL Assignee Company: Merck Patent Gmbh; Frankfurter Strasse 250, 64293 Darmstadt (DE) Disease Area: Alzheimer, s disease Biological Target: Inhibition of the glycosidase O-GlcNAcase (OGA) Summary: The invention in this patent application relates to compounds represented generally by formula (I), which exhibit activities as glycosidase inhibitors that can inhibit O-GlcNAcase. These compounds may potentially be used for slowing the progression and/or the treatment of Alzheimer, s disease (AD) and possibly other diseases.

Many nuclear and cytoplasmic cellular proteins undergo several dynamic (reversible) modifications during their lifetime in which the monosaccharide 2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetyl glucosamine) is attached and removed. The forward process is a glycosylation in which β-N-acetyl glucosamine is attached to specific serine and threonine residues on proteins via a post-translational O-glycosidic linkage to form O-linked N-acetylglucosamine (O-GlcNAc) proteins. This process is catalyzed by an enzyme called O-GlcNAc transferase (OGTase). The O-GlcNAc modification is abundant in the brain and was found on many cytoskeletal proteins, such as neurofilament proteins, synapsins, synapsin-specific clathrin assembly protein AP-3, and Ankyrin-G. The O-GlcNAc-modified proteins are responsible for the regulation of a wide range of vital cellular functions such as transcription, proteasomal degradation, and cellular signaling. The reverse process is a hydrolysis to cleave the β-N-acetyl glucosamine attachments and liberate the proteins. The cleavage of the O-GlcNAc is catalyzed by a glycosidase known as O-GlcNAcase or OGA, which is a member of family 84 of glycoside hydrolases. The development of neurofibrillary tangles (NFTs) is one of the characteristics of neurodegenerative diseases such as AD, Downs, syndrome, Pick, s disease, Niemann-Pick Type C disease, and amyotrophic lateral sclerosis (ALS). NFTs are aggregates of paired helical filaments (PHFs) made of an abnormal form of the cytoskeletal protein tau. In its normal function, tau stabilizes a key cellular network of microtubules that is essential for distributing proteins and nutrients within neurons. However, tau becomes hyperphosphorylated in AD patients to form PHFs and then aggregates to form NFTs. While the exact causes of hyperphosphorylation of tau are unknown, there is a clear correlation between the levels of NFTs and the severity of dementia in AD patients, which is indicative of a key role for tau dysfunction in AD. Considerable studies were directed toward understanding the causes, as well as identifying strategies to reduce tau hyperphosphorylation in order to halt or reverse the progression of AD. Some of these studies have shown a significant connection between the levels of O-GlcNAc modification and the phosphorylation of tau. A key observation was that O-GlcNAc modification occurs on many proteins at the same amino acid residues that can also be phosphorylated. Also, the hyperphosphorylated tau in human AD brains contains noticeably lower levels of O-GlcNAc than the levels found in healthy brains. It appears that there is a reciprocal relationship between the levels of O-GlcNAc modification and phosphorylation of tau; increased phosphorylation levels are accompanied by decreased O-GlcNAc levels and vice versa. This reciprocal relationship between O-GicNAc and phosphorylation was named the Yin-Yang hypothesis. The hypothesis was supported by the discovery that the enzyme OGTase forms a functional dynamic complex with phosphatases. This indicates that it is …