Inhibitors and modulators of beta- and gamma-secretase.

Most gene mutations associated with Alzheimer's disease point to the metabolism of amyloid precursor protein as potential cause. The beta- and gamma-secretases are two executioners of amyloid precursor protein processing resulting in amyloid beta. Significant progress has been made in the selective inhibition of both proteases, regardless of structural information for gamma-secretase. Several peptidic and non-peptidic leads were identified and first drug candidates are in clinical trials. This review focuses on the developments since 2003.

Drug development and PET-diagnostics for Alzheimer's disease.

The exact cause of Alzheimer's disease is still unknown; despite the dramatic progress in understanding. Most gene mutations associated with Alzheimer's disease point to the amyloid precursor protein and amyloid beta. The alpha-, beta- and gamma-secretases are the three executioners of amyloid precursor protein processing. Significant progress has been made in the selective inhibition of these proteases, regardless of the availability of structural information. Several peptidic and non-peptidic leads were identified and first drug candidates are in clinical trials. Cholesterol lowering drugs and metal chelators are also in advanced clinical stages as disease modifiers. Successful trials demand either large cohorts or reliable markers for Alzheimer's disease. Therefore, several radiomarkers are under investigation to support such clinical trials.

Ensemble-docking approach on BACE-1: pharmacophore perception and guidelines for drug design.

Beta-secretase (BACE-1), a key enzyme in the etiopathogenesis and progression of Alzheimer disease, is the focus of medicinal chemistry efforts both in the pharmaceutical industry and in academia. Despite the availability of diverse peptidomimetic BACE-1 inhibitors, nonpeptidic compounds suitable for oral delivery and transport across the blood brain barrier are in great demand. Herein, a number of active and structurally diverse inhibitors were selected and subjected to an ensemble-docking process into five BACE-1 X-ray structures. The calculated bioactive conformations of these inhibitors allowed us to build an exhaustive pharmacophore model, which captures both the common geometric and electronic features essential for enzyme inhibition. The model is intended to aid the rational design of new BACE-1 inhibitors. Furthermore, a comparison of BACE/cathepsin D X-ray structures was made to provide guidelines for the design of BACE-selective inhibitors.

Modulators and inhibitors of gamma- and beta-secretases.

Most gene mutations associated with Alzheimer's disease point to the metabolism of amyloid precursor protein as a potential cause. The beta- and gamma-secretases are two executioners of amyloid precursor protein processing resulting in amyloid-beta. Significant progress has been made in the selective inhibition of both proteases, regardless of structural information for gamma-secretase. Several peptidic and nonpeptidic leads were identified for both targets.

Tripeptide mimetics inhibit the 20 S proteasome by covalent bonding to the active threonines.

Proteasomes play an important role in protein turnover in living cells. The inhibition of proteasomes affects cell cycle processes and induces apoptosis. Thus, 20 S proteasomal inhibitors are potential tools for the modulation of neoplastic growth. Based on MG132, a potent but nonspecific 20 S proteasome inhibitor, we designed and synthesized 22 compounds and evaluated them for the inhibition of proteasomes. The majority of the synthesized compounds reduced the hydrolysis of LLVY-7-aminomethylcoumarin peptide substrate in cell lysates, some of them drastically. Several compounds displayed inhibitory effects when tested in vitro on isolated 20 S proteasomes, with lowest IC(50) values of 58 nm (chymotrypsin-like activity), 53 nm (trypsin-like activity), and 100 nm (caspase-like activity). Compounds 16, 21, 22, and 28 affected the chymotrypsin-like activity of the beta5 subunit exclusively, whereas compounds 7 and 8 inhibited the beta2 trypsin-like active site selectively. Compounds 13 and 15 inhibited all three proteolytic activities. Compound 15 was shown to interact with the active site by x-ray crystallography. The potential of these novel inhibitors was assessed by cellular tolerance and biological response. HeLa cells tolerated up to 1 microm concentrations of all substances. Intracellular reduction of proteasomal activity and accumulation of polyubiquitinated proteins were observed for compounds 7, 13, 15, 22, 25, 26, 27, and 28 on HeLa cells. Four of these compounds (7, 15, 26, and 28) induced apoptosis in HeLa cells and thus are considered as promising leads for anti-tumor drug development.