Secretase Enzyme Inhibitors

(3-Amyloid Inhibitory Agents A. (3-Secretase Enzyme Inhibitors 

Assignee Elan Pharmaceuticals, Inc. and Pharmacia Upjohn Company 

Invention Significance The presence of (3-amyloid plaques is a defining 

A-f-Butoxycarbonylphenylalanine methyl ester (3.6 mmol) was dissolved in 15 ml toluene, then cooled to -78° C, and treated with the dropwise addition of 9.0 ml 1M solution of diisobutylaluminum hydride in toluene over 5 minutes. After 1 hour, the reaction was slowly quenched with 1 ml methyl alcohol, and then poured into a cooled aqueous solution of potassium sodium tartrate. The mixture was stirred 2 hours, then extracted with diethyl ether, washed with water and brine, dried over Na2S04, and concentrated to a colorless oil. The oil was purified by chromatography using silica gel with 20% EtOAc/heptane and the product isolated in 88% yield as a white solid. 

AI-f-Butoxycarbonylalanine (10 mmol) dissolved in THF was treated with carbonyldi-imidazole (12 mmol), then the mixture stirred 50 minutes, and further treated with isobutylamine (20 mmol). After stirring 1 week, the mixture was concentrated and the residue dissolved in EtOAc. It was then washed with aqueous KHS04, water, and brine, dried using Na2S04, and the product isolated as a white solid in 83% yield. 

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Hydroxyethylene analogs, (I), effective as (3-secretase enzyme inhibitors prepared by Horn (2) were effective in treating amyloid plaques and slowing the progression of Alzheimer s disease. 

Schostarez (3) prepared aza-hydroxylethyl derivatives, (II), which were effective as (3-secretase enzyme inhibitors in the treatment of amyloid-related diseases. 

In subsequent investigations by Schostarez (4), diaminediol derivatives, (III), effective as (3-secretase enzyme inhibitors were prepared, which were effective in reducing amyloid peptide formation and used in treating dementia and neurodegenerative disorders. 

Lactones, (IV) and (V), prepared by Wu (5) and Audia (6), respectively, were effective as (3-secretase enzyme inhibitors and useful in treating Alzheimer s disorder. 

Amide, (VI), derivatives of the current invention prepared by Horn (7) were also effective as (3-secretase enzyme inhibitors and used in treating Alzheimer s disease. 

In the search for novel and effective therapeutics for the treatment of HCV, HCV protease inhibitors are not the only class of enzyme inhibitor to which macrocyclization strategy has been applied. Thus, macrocyclic inhibitors of the HCV NS5B polymerase have also been explored (Section 7.6.1). In addition, macrocyclic analogs of acyclic inhibitors of proteases including. Factor XIa, HIV protease, renin and beta-secretase have been investigated. Examples of each of these are briefly discussed in Section 7.6.2. 

These must be worthwhile objectives and the recent identification by a number of research groups (see Skovronsky and Lee 2000 for description and details) of P-secretase as the membrane-bound aspartyl protease (RACE), S-site APP cleaving enzyme, paves the way for developing possible chemical inhibitors of its activity for experimental and clinical evaluation, although that remains for the future. 

Involvement of several proteolytic enzymes, secretases, is probably crucial for this process but other hypotheses, including, for example, cholinergic transmission or accumulation of metal ions, have also been considered. Future perspectives in this area concern the search for novel pharmaceuticals that cross the blood-brain barrier, without side effects (e.g., the dyskinesias of L-Dopa), or potent and selective inhibitors of improper cleavage of amyloid protein, or even stem cell therapy to restore neuronal cells. 

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