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Drugs for Treatment of Alzheimer’s Disease

#4032


Enantiomerically Pure None-Proteinogenic Amino Acids, Peptides and their Derivatives as Multi-Target Directed Ligands for Treatment of Alzheimer’s Disease

Tech Area / Field

  • MED-DRG/Drug Discovery/Medicine
  • BIO-CHM/Biochemistry/Biotechnology
  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry

Status
3 Approved without Funding

Registration date
12.02.2010

Leading Institute
INEOS (Organo-Element Compounds), Russia, Moscow

Supporting institutes

  • Yerevan State University, Armenia, Yerevan\nInstitute of Physiologically Active Substances, Russia, Moscow reg., Chernogolovka

Collaborators

  • Universite de Paris-Sud / Institut de Chimie Moleculaire et des Materiaux D’Orsay, France, Orsay\nUniversite de Nantes / Laboratoire de Biotechnologie, France, Nantes\nUniversity of Newcastle, UK, Newcastle upon Tyne\nUniversiteit Maastricht / School for Mental Health and Neuroscience, The Netherlands, Maastricht

Project summary

Alzheimer’s disease (AD) is the most debasing human illness, leading to senile dementia of elderly people over 65 years of age. The disease leads to the final destruction of neurons and inevitable death of the patient within several years. It was estimated that more than 15 millions of people is now affected by AD worldwide. As the life span of humans seems to increase all over the world, the growth in number of AD effected people acquires the proportion of an epidemic and economic disaster. Thus, the AD drug or drugs are urgently needed. Unfortunately, the present day therapy of AD addresses only its symptoms and unable to cure the real cause or causes of the malady.

We put ourselves a task of developing a novel family of AD drugs based on one molecule, multiple targets paradigm.

For this purpose, we plan:

  1. To develop simple enantiomerically pure dipeptides analogues to (R)-Trp-aib developed by Prof. Gazit to block oligomerization of soluble amyloid Aβ peptides. Compound 8 (Fig. 5) has (R)-α-Naphtylalanine (or (R)-β-Naphtylalanine) moiety introduced instead of (R)-Trp fragment. The change should impart additional oxidative stability to the dipeptide, retaining its hydrophobic nature. In order to overcome solubility problems, one of the Me groups (or possibly both) of Aib will be substituted with -CH2OH moieties (compounds 9, and 10, Fig. 5).
  2. Compound 11 will contain benzimidazole moiety (see Fig. 5), hopefully retaining the lypophilic nature of the original Gazit’s dipeptide and imparting a positive charge to it under the physiological conditions
  3. Compound 12 will contain hydroquinone moiety (Fig. 5), imparting reductive properties to the peptide in analogy with Prof. Melhiorre system (Fig. 4) in order to address reactive oxygen species (ROS) problem.
  4. The family of type 13 compounds is a novel type of zwitterionic (R)- or (S)-amino acid derivatives earlier introduced by some of us. Introduction of positive charge onto some of the aromatic moieties (see Fig. 5) might create special affinity of the peptide to tau proteins, preventing their hyperphosphorylation or be active in inhibiting human AChE. In addition, the compounds are likely NHC type chelating agents for soft metal ions under the physiological conditions.

The screening of the new synthesized compounds will include.
  • During the primary screening testing the ability of compounds to block the oligomerization and fibrillation of synthetic Aβ will be estimating by the set of methods.
  • Influence on β-amyloid toxicity will be investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) toxicity assay on rat brain cortex culture cells or(and) neuroblastoma cells and additional testing of compounds influence on β-amyloid-induced impairment of mitochondrial functions, calcium homeostasis and oxidative stress will be provided for leader compounds.
  • For the most perspective compounds the assays of their potential cognition-stimulating and neuroprotective properties as on normal animals and also on β-amyloid or AF64a – neurotoxic model of Alzheimer disease [Walsh T. and Opello K. in: «Toxin-Induced Models of Neurological disorders» – Eds. Woodruff M., A. Nonneman – N-Y., “Plenum Press”, 1994, P. 259-279] will be performed.
  • Also we plan to study the leader compouns neuroprotective and cognition-stimulated properties on transgenic mice with the Swedish (K670N/M671L) and Indiana (V717F) mutations of APP and total Aβ and Aβ1-42 overexpression in neocortical and hippocampus (B6.Cg-Tg(PDGFB-APPSwInd)20Lms/2J).

In case of a successful completion of the project, the lead compound or compounds will be suggested for clinical trials.

The synthetic approach to the preparation of the enantiomerically pure amino acids was earlier developed by Belokon’s Moscow group and was being used by many groups all over the world. It is based on use of nickel(II) complex [(S)- or
(
R)-BPB-Gly-NiII] of the Schiff’s base derived from glycine and (S)- or (R)-2-(N-benzylprolyl)aminobenzophenone (BPB). The alkylation or aldol condensation of the glycine moiety in presence of bases produce alkylated complexes which can be easily decomposed and the target enantiomerically pure (S)- or (R)-amino acid recovered. (S)- or (R)-BPB is a chiral auxiliary that can be also recovered and reused after a particular alkylation reaction was complete (see Fig. 7 for the general outline of the reactions).

A novel highly efficient catalytic methodology of asymmetric synthesis of amino acids was developed by the Moscow and Yerevan teams with the previous financial support of ISTC (Grants ## 2780 and A-356).

Peptides are supposed to be synthesized by a traditional peptide synthesis (in solution), employing methods of activated esters and N or O-protective groups (benzyl, tert-butyl, etc.).


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