-Secretase inhibitors & modulators

-Secretase is involved in the pathogenesis of Alzheimers disease and is a top target for therapeutic intervention. It is essential for the generation of the 42 aminoacid amyloid beta peptide(A42) which is considered to be the key player in AD pathogenesis and is the main constituent of the amyloid plaques found in AD brains. -Secretase also cleaves numerous other substrates, raising concerns about -secretase inhibitor off-target effects. -secretase modulators, alter the cleavage site of -secretase on amyloid precursor protein and are thus a promising therapeutic approach for Alzheimers disease.

THE -SECRETASE COMPLEX

It consists of 4 proteins: 1. Nicastrin 2. Anterior pharynx-defective 1(APH1) 3. Presenilin 4. Presenilin enhancer protein 2(PEN2) Presenilin is essential for activity and the three other proteins are thought to be involved in maturation and stability of the complex. Nicastrin has recently been demonstrated to be important in substrate recognition.

 Presenilin NTF and CTF contribute to the binding site The enzyme apparently contains an initial docking site for the transmembrane region of the substrate that is distinct from the active site Findings suggest that the docking site, like the active site, is at the interface between the two presenilin subunits and implies that substrate passes, in whole or in part, between these subunits to access the internal active site.

-SECRETASE INHIBITORS
-secretase has proved to be a highly tractable target for AD drug treatment, at least w.r.t. the development of orally bioavailable, brain-penetrant secretase inhibitors (GSIs) Multiple orally bioavailable, brain-penetrant GSIs have been identified; however, target-based toxicity has been a major obstacle to the clinical development of these compounds. The -secretase enzyme processes numerous other transmembrane proteins in addition to APP; for eg, -secretase processing of Notch1 is crucial for notch signaling. Nonselective GSI treatment leads to a variety of toxicities related to notch inhibition, including, but not limited to, gastrointestinal, skin and immune system abnormalities.

-SECRETASE INHIBITORS

Developed by Elan and Eli Lilly Potently inhibited A production in cells High single oral doses (100 mg/kg) were needed to observe 50% A lowering in the brains

 Sulfonamide inhibitor developed by Bristol-Myers Squibb (BMS) and the former SIBIA Inhibits A production in HEK293 cells stably overexpressing APP. To be selective for inhibiting the processing of APP over Notch, hence said to be Notch sparing.

 Benzodiazepine analogue developed at Eli Lilly one of the most potent -secretase inhibitors yet reported for inhibiting A production in APP-overexpressing HEK293 cells after a 10 mg/kg dose, brain and CSF A levels were completely knocked down and did not recover 24 h after dosing

LY-450139 Benzolactam developed at Eli Lilly less potent than LY-411575 this compound has moved into clinical trials, and so far it is the only -secretase inhibitor for which human trials have been reported. In initial human trials in healthy volunteers,58,59 single doses of LY-450139 of up to 140 mg were apparently safe and reduced plasma A levels by up to 72.6%. However, steady state A in the cerebral spinal fluid was not affected, and it is unclear if higher doses can lower brain A and without Notch-related side effects.

-SECRETASE MODULATORS
Another important class of drugs, -secretase modulators (GSMs), alter the cleavage site of -secretase on APP, changing the A42/40 ratio, and are thus a promising therapeutic approach for AD. A42-reducing GSMs not only decrease levels of A42, but also increase levels of shorter A peptides. Although GSMs have been reported to have varying effects on substrates other than APP, they do not seem to inhibit signaling events mediated by these substrates. Thus, GSMs seem to avoid targetbased toxicity.

 Among the first reported modulators were isocoumarin JLK compounds, which blocked A production at the secretase level but did not affect Notch processing. However, the direct target of these compounds remains unclear. But, recent studies suggest that the protease complex contains allosteric binding sites that can alter substrate selectivity and the sites of substrate proteolysis.

 Certain non-steroidal anti-inflammatory drugs (NSAIDs) can reduce the production of the highly aggregation-prone A42 peptide and increase a 38-residue form of A. The biochemical mechanism of these NSAID g-secretase modulators is unclear. The site of cleavage within the Notch transmembrane domain is similarly affected, but this subtle change does not inhibit the release of the intracellular domain and thus does not affect Notch signaling.

 Tarenflurbil (R-flurbiprofen), the first Gsm to be evaluated in humans, was shown to be safe in the long term but recently failed in phase III clinical trials. This failure was possibly due to low potency ascribed to the compound and poor CNS penetration.

 Other allosteric modulators resemble kinase inhibitors and interact with a nucleotide binding site on the -secretase complex. The discovery that ATP can increase A production in membrane preparations prompted the testing of a variety of compounds that interact with ATP binding sites on other proteins. In this focused screen,Gleevec,an Abl kinase inhibitor emerged as a selective inhibitor of A production in cells without affecting the proteolysis of Notch.