Alzheimer's disease is a neurodegenerative disease characterised by a progressive decline in cognitive function. It has a complex pathophysiology explained by several related hypotheses. The characteristic changes in the central nervous system are the deposition of amyloid plaques and neurofibrillary tangles. The concentration of the neurotransmitter acetylcholine is reduced, cholinergic neurons decline and neuroinflammation is present.
Currently, drugs that slow down the development of the disease are available and they have several side effects. There are no low-molecular-weight disease modifying drugs available. Targeting multiple targets simultaneously could be a reasonable and attractive approach for Alzheimer's disease treatment. In my master's thesis we designed, synthesised and biochemically evaluated four compounds that selectively inhibit the enzyme human butyrylcholinesterase and the enzyme mitogen-activated protein kinase p38α by an innovative approach called multi-target-directed ligands. Butyrylcholinesterase activity is increased in Alzheimer's disease, reducing acetylcholine levels. Mitogen-activated protein kinase p38α plays an important role in neuroinflammation.
The design was based on the compound OSF-267, a selective dual inhibitor of butyrylcholinesterase and mitogen-activated protein kinase p38α. For all compounds, the dimethylamine fragment, the 2,4-difluorophenoxy group and the indazole ring were retained. We have modified the isobutyl fragment at site 1 of the indazole ring and substituted it for hydroxyalkyl chains, piperidine and Boc protected piperidine. All four compounds showed selective butyrylcholinesterase inhibition in low micromolar range. This would have the beneficial effect of reducing the potential for peripheral parasympathetic side-effects caused by acetylcholinesterase inhibition, which limits treatment with existing drugs. Two compounds exert inhibitory activity on the mitogen-activated protein kinase p38α comparable to OSF-267. The other two compounds are less potent inhibitors.
Overall, these two later compounds appear to be most promising for further development as, in addition to their inhibiting action on both targets, they have a hydroxyl group in their structure to which alkyl and polyethylene glycol linkers can be attached by simple organic chemistry steps. Further development of chimeric degraders exploiting the ubiquitin-proteasome system for proteolytic degradation of target proteins would thus be possible. This is an innovative approach that attempts to modify pathophysiological disease processes that cannot be targeted by classical small molecule drugs.
|
