Umbreen, Sumaira (2007)
Synthesis and Biological Evaluation of β-Secretase Inhibitors, Proteasome Inhibitors and Losartan Active Metabolites.
Technische Universität Darmstadt
Dissertation, Erstveröffentlichung

Kurzbeschreibung (Abstract)

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, presenting itself clinically by progressive loss of memory and learning and its prevention is a major public health challenge. The key event in the progression of AD are the sequential cleavages of β-amyloid precursor protein (β-APP) by two proteolytic enzymes, beta-site APP-cleaving enzyme 1 (BACE-1 or memapsin 2) and γ-secretase to produce Aβ40 and Aβ42 in the human brain. From the therapeutic point of view, BACE-1 appears to be a promising drug target, which stimulated the design and synthesis of BACE-1 inhibitors. The present work describes the design, synthesis and biological evaluation of non-peptidic, semi-peptidic and peptidic BACE-1 inhibitors. The norstatine based BACE-1 inhibitors were synthesized to study the structure-activity relationship (SAR) at the P2´ position. The synthetic approach utilized L-phenylalaninol and isophthalamide derivatives, provided both hydroxyl diastereomers in a 1:1 ratio, which were isolated and investigated separately. To enable lead optimization and facile variation at the P1 position, a new synthetic route was developed by employing an organocatalytic approach. As a consequence, a variety of norstatine derivatives was synthesized by a proline catalyzed α-amination reaction followed by a Passerini reaction. For an easy removal of catalyst, clean and straightforward separation of the product, an immobilized proline derived catalyst was synthesized and successfully employed. A series of compounds was designed and synthesized as potential BACE-1 inhibitors, as analogues of MG132, which is known to have a broad specificity to inhibit cysteine, serine and aspartyl proteases. Biological evaluation of these compounds for BACE-1 and 20S proteasome displayed moderate BACE-1 inhibition. However, they turned out to be potent 20S proteasome inhibitors and promising drug candidates. The most potent 20S proteasome inhibitor BSc2118 that has low toxicity and effective inhibition encouraged further evaluation and optimization of the lead compound. The combined treatment of BSc2118 and calpain-specific inhibitor was evaluated on human melanoma cisplatin-resistant (MeWocis1) cells and found to affect two different proteolytic pathways, which can enhance the proteasome inhibitor–mediated death of the tumor cells, especially of the cisplatin-resistant cells. An agonist of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) acts to improve behavioural performance in an animal model of AD. Atherosclerosis, coronary heart disease and hypertension are identified as other risk factors for AD. A subgroup of angiotensin receptor type 1 (AT1) receptor blockers has been identified as ligands for the PPAR-γ. Therefore, two active losartan metabolites i.e. EXP3174 and EXP3179 were synthesized and characterized for the PPAR-γ–activating properties in the present work. Moreover, it was investigated that EXP3179 inhibits collagen-dependent platelet activation via glycoprotein receptor-VI independent of AT1-receptor antagonism, which has a potential impact on atherothrombosis. Beside this, it was explored that AT1 blockade in astrocytes decreases hypoxia-induced cell damage and inflammation. AT1-R blockade could be of therapeutic benefit during neurodegenerative disorders accompanied by inflammation, such as Alzheimer’s disease, Parkinson’s disease, stroke and multiple sclerosis due to its anti-inflammatory and vulnerability-reducing effect on astrocytes.

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