pf-3084014 and Alzheimer-Disease

Alzheimer's disease (AD) is a neurodegenerative disease, characterized by progressive loss of memory which is associated with other cognitive deficits. The two protein structures in the brain i.e. neurofibrillary tangles and senile plaques are considered to hamper the normal cognitive activity of the brain. There are various therapeutic interpolations under investigation to thwart and treat AD. Secretases inhibitors are important agents that inhibit the development of senile plaques. β-secretase (BACE) inhibitors are in lime light for the drug development of AD. BACE initiates the production of Aβ, so its inhibition provides a valid target for the AD. BACE inhibitors viz. LY2811376, LY2886721, E2609 are in different phases of clinical trials. However, chemical study of MK8931 was discontinued due to lack of chances of finding a positive clinical effect.. The review incorporates exhaustive literature reports on secretase inhibitors, γ-secretase modulators (GSMs) and α-secretase enhancers. The recent studies on the natural products as GSMs have also been included.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Enzyme Inhibitors; Humans; Plaque, Amyloid

Several lines of evidence indicate that the production and deposition of amyloid-beta peptides (Abeta) contribute to the etiology of Alzheimer's disease. Inhibition or modulation of gamma-secretase, that is a responsible enzyme for the Abeta production, is one of the plausible therapeutics for Alzheimer's disease. However, the gamma-secretase is an unusual aspartic protease that cleaves the scissile bond within the transmembrane domain of several membrane protein including APP and Notch receptor. Thus, development of drugs that regulate the production of Abeta without affecting the Notch signaling is now demanding. Extensive drug screening and development allow that some secretase inhibitors and modulators have advanced into late-phase clinical trials, whereas the molecular mechanisms of Notch-sparing effect by these compounds effect still remain unknown. Identification of the molecular targets and mechanisms of these compounds using chemical biological approaches is currently underway. This review focuses on the recent development of inhibitors/modulators and provides a direction for the effective treatment of AD through inhibition/modulation of the gamma-secretase activity.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Clinical Trials as Topic; Drug Design; Enzyme Inhibitors; Humans; Sulfonamides; Tetrahydronaphthalenes; Thiophenes; Valine

Topics: Adult; Alanine; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Azepines; Biopsy; Female; Hidradenitis Suppurativa; Humans; Male; Mice; Mice, Knockout; Tetrahydronaphthalenes; Valine