O1-10-01: preclinical profiles of drug candidates promoting o-linked glycosylation of tau for the treatment of alzheimer's disease and tauopathies

One of the major hallmarks of Alzheimer's disease (AD) and tauopathies is the presence of neurofibrillary tangles (NFTs) in the brain. NFTs are composed of aggregates of the microtubule associated protein tau, and NFT pathology appears to be closely associated with neurodegeneration. The progression of NFT pathology correlates with the cognitive decline in AD and mutations in tau are causative of frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Since NFT pathology can be modified by inhibition of O-GlcNAcase, this enzyme is an attractive drug target. Mechanistically, O-GlcNAcase inhibition blocks the removal of O-linked N-acetylglucosamine (O-GlcNAc) moieties from serine and threonine residues. This leads to an accumulation of O-GlcNAcylated tau protein that is less prone to aggregation into toxic oligomers and NFTs. Starting from a series of novel and non-carbohydrate O-GlcNAcase inhibitors a focused medicinal chemistry lead optimization campaign was performed. Candidate molecules with improved potency, drug-like pharmacokinetic and pharmacodynamics profiles were identified using a stringent assay cascade. Several candidate molecules were identified during the lead optimization campaign. The front runner ASN-461 has been identified as the most advanced preclinical development candidate. ASN-461 has good potencies for inhibition of the recombinant and cellular O-GlcNAcase enzyme (18 nM) and excellent brain penetration. This O-GlcNAcase inhibitor displays a high selectivity for its target and does not inhibit hexosaminidase A/B which is the most important antitarget for this approach. ASN-461 demonstrated a saturable in vivo response utilizing O-GlcNAcylation of brain protein as readout for CNS target engagement. The maximum effect was obtained at a 10 mg/kg single oral dose with an ED50 of 2.2 mg/kg and was fully reversible after 24 hours. The preclinical package supporting the investigation of ASN-461 in GLP toxicity studies is currently being collected. Inhibition of O-GlcNAcase is an attractive approach for the development of a modifier of tau pathology in humans. O-GlcNAcase inhibitors are expected to have far reaching clinical utility from Alzheimer's disease to tauopathies that are mainly driven by the accumulation of tau. ASN-461 has an interesting preclinical profile with the potential to enter human Phase I safety and tolerability studies in 2015.