Inhibitors secretase

Subcutaneous application of 100 mg kg-1 to mice resulted in a 50% reduction of A/ brain levels after 3 h. The reduction was 40% 3 h after an oral dose of 100 mg kg-1. Further development of the compound by Eli Lilly included stereoselective placement of the hydroxyl group and locking of the spatial arrangement of two phenyl rings in a seven-membered lactam to yield 17 (LY 411575, HEK IC50 1 nM). 

After several failures with peptidic structures such as 2, all of which suffered from toxicity problems during development, Bristol Myers Squibb and Merck [32] published details of almost 1000 derivatives of 4-chloro-N-(2,5-difluorophenyl)-benzenesulfonamides. Five-hundred of these were reported to be very good in- 

---

Dtugs in clinical development that directly target the A(3 pathway are at an early stage. Inhibitors of (3- and y-secretases that can lower the A 3 production have entered clinical phase trials with (3-secretase inhibitors being years behind the development of y-secretase inhibitors. Functional y-secretase inhibitors have been shown to reduce the rate of A 3 formation in vitro and in vivo. The reduction of A 3 monomer levels could prevent oligomer formation and subsequent syn-aptotoxicity. Numerous anti-amyloid approaches to... 

Figure 8.20 (A) Generic chemical structure of the y-secretase inhibitors described by Seiffert et al. (2000). (B) y-Secretase inhibitor incorporating a benzophenone photoaffinity label for crosslinking studies.

Zhang, D., Hanson, R., Roongta, V. et al. (2006) In vitro and in vivo metabolism of a gamma-secretase inhibitor BMS-299897 and generation of active metabolites in milligram quantities with a microbial bioreactor. Current Drug Metabolism, 7, 883-896. 

The sustained attractiveness of photolabeling is apparent from its prominence in studies of y-secretase, an intramembrane protease that contributes to forming amyloid-p peptides and is a major target in Alzheimer s disease [60-62]. y-Secretase is a complex of at least four different polypeptides, and is difficult to engage with high-resolution structural methods. However, in a case of this kind that involves a known target, immunodetection of proteins can often specify the target of y-secretase inhibitor photoaffinity probes such as 19, and proteomic mass spectrometry is not needed. 

Table 2 Effects of fluorine on the properties of gamma-secretase inhibitors... 

Cyclic sulfamides 326 serve as key intermediates in the synthesis of a series of potent and selective y-secretase inhibitors with potential for the treatment of Alzheimer s disease. 

Secretase Inhibitors and Modulators for the Treatment of Alzheimer s Disease... 

Numerous y-secretase inhibitors featuring sulfonamide- and sulfone-based scaffolds have been disclosed. Bicyclononane thiophene sulfonamide 40 reduced brain Ap in transgenic mice by 50% after a dose of 100 mg/kg [100]. High potency (A p IC50 = 0.5 nM) and improved oral activity (ID50 = 17 mg/kg) was found in a series of related sulfamides represented by 41 [101]. Tetrahydroquinoline (42) and piperidine (43-44) sulfonamides have been developed [102-104]. Elaboration of the piperidine series with the cyclopropyl substituent present in 44 improved in vitro potency (Aft IC50 = 2.1 nM in membrane assay) and in vivo activity in transgenic mice (plasma Ap = 2% of control after oral dose of 30 mg/kg). Reductions of A p in the cortex were reported to be comparable to those observed in plasma. 

Sulfone-based y-secretase inhibitors including cyclohexane 45 (Ap IC50 = 3nM) have been reported [105]. Variations on this series include 3- and 4-substituted analogs such as 46 and 30, and highly potent bicyclic systems such as 47 (Ap IC50 = 0.06 nM), which was found to lower brain Ap in mice with an ED50 of 3.9mg/kg [106-108]. Piperidine sulfone 48 resulted from modification of hits from a pharmacophore-based computational search [109]. 

Novel PS-related famihes of proteins (IMPAS/PSH/signal peptide peptidases [SPSs]) have been identified (163). Intramembrane protease-associated or intramembrane protease aspartic protein Impas 1 (1MP1)/SPS induces intramembranous cleavage of PSl holoprotein in cultured cells coexpressing these proteins. Mutations in evolutionary invariant sites in hlMPl or specific y-secretase inhibitors abolish the hlMPl-mediated endoproteolysis of PSl. In contrast, AD-like mutations in neither hlMPl nor PSl substrate abridge the PSl cleavage (163). 

---