Multiligands approaches for the developing neuroprotective agents for Alzheimer’s disease

During past 15 years any new agent that was investigated
in clinical trials on Alzheimer’s disease (AD) patients
have not been approved for the market. The same situation
take place with agents for amyotrophic lateral sclerosis
(ALS) therapy. One of the main problem in successful
development of the agents for CNS neurodegenerative
disorders treatment related to multifactorial nature of
such diseases. In this relation, focused design of multitarget
drugs that simultaneously act on several biotargets
connected to pathogenesis of neurodegenerative diseases
looks as a promising strategy for the developing new generation
of neuroprotective CNS agents [1]. In the present
work the results of design and synthesis of novel polypharmacophore”
agents superposing in one molecule
several structural pharmacophore fragments of already
validated neuroprotective agents are presented. In particular,
synthesis and study of conjugates of phenothiazine
(methylene blue) and gamma-carboline (Dimebon) derivatives,
as well as conjugates of adamantane (memantine)
and carbazole derivatives was performed [2-4]. In particular,
in series of adamantane-containing indole derivatives
compounds with unique combination of mitoprotective
and anti-aggregation properties were revealed [5]. It was
also shown that these compounds manifested their efficacy
for preventing and delaying of neuropathological
symptoms on amyotrophic sclerosis animal models [6].