title: Semagacestat, a gamma-secretase inhibitor for the potential treatment of Alzheimer's disease.
abstract: Eli Lilly & Co is developing semagacestat, an inhibitor of the gamma-secretase enzyme. This enzyme is pivotal in the generation of beta-amyloid (A beta), a neurotoxic endogenous peptide believed to be involved in the pathogenesis of Alzheimer's disease (AD). In animals, semagacestat reduced A beta levels in the plasma, CSF and brain; however, studies have not reported on cognitive effect of this compound. Phase I clinical trials in healthy volunteers have evaluated doses ranging from 5 to 140 mg/day and phase II trials in patients with AD have evaluated doses ranging from 30 to 140 mg/day for up to 14 weeks. Trials in both healthy volunteers and patients with AD have demonstrated a dose-dependent inhibition of plasma A beta levels, and a recent trial in healthy volunteers demonstrated a robust, dose-dependent inhibition of newly generated A beta in the CSF after single oral doses. The main adverse events involved the gastrointestinal tract. In 2008, two large phase III clinical trials in patients with mild-to-moderate AD were initiated by Eli Lilly. Semagacestat is the most advanced gamma-secretase inhibitor and represents a major hope among therapies designed to slow the rate of cognitive decline of patients with AD.
authors: Chiesi Farmaceutici SpA, Research & Development Department, Via Palermo 26/A, 43100 Parma, Italy. b.imbimbo@chiesigroup.com
authors: Bruno P
authors: BP
authors: Imbimbo
authors: Ilaria
authors: I
authors: Peretto
mesh_terms: D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001381:Azepines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D015507:Drugs, Investigational / Q000627:therapeutic use*; D006801:Humans; D015394:Molecular Structure; D010330:Patents as Topic; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D015507:Drugs, Investigational; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine