title: Prospects of β-Secretase Inhibitors for the Treatment of Alzheimer's Disease.
abstract: β-Secretase continues to be an attractive drug discovery target for the therapeutic intervention of Alzheimer's disease (AD). This enzyme plays a critical role in the production of neurotoxic β-amyloid (Aβ) peptides in the brain. Over the years, extensive research efforts have led to the development of many promising classes of inhibitors against this protease. Many small-molecule, peptidomimetic, and nonpeptide β-secretase inhibitors have now overcome the key challenging development hurdles such as selectivity and brain penetration. A number of inhibitors have also shown further promise in reducing brain Aβ and rescuing cognitive decline in animal models. Recently, several β-secretase inhibitors have entered into preclinical and phase I studies, and at least one of these inhibitors has advanced to phase II/III human trials. The outlook on β-secretase inhibitor drugs for the treatment of AD patients is discussed herein.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907 (USA). akghosh@purdue.edu.|Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 (USA). akghosh@purdue.edu.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Protein Studies Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104 (USA).
authors.forename: Jordan
authors.initials: J
authors.lastname: Tang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007093:Imidazoles; C569204:LY2811376; D011480:Protease Inhibitors; D011743:Pyrimidines; D013141:Spiro Compounds; D013843:Thiazines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human; C000608388:lanabecestat
keywords: Alzheimer’s disease; BACE1; BACE2; cathepsin D; memapsin 2; protease inhibitors; β-secretase