title: Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease.
abstract: The presenilin containing gamma-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. gamma-Secretase catalyzes the final step in the generation of Abeta(40) and Abeta(42) peptides from APP. Amyloid beta-peptides (Abeta peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic Abeta peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide gamma-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits Abeta production with low nanomolar potency in cellular and cell-free assays of gamma-secretase function, and displaces a tritiated analog of GSI-953 from enriched gamma-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid Abeta levels, and a reversal of contextual fear-conditioning deficits that are correlated with Abeta load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dose-dependent changes in plasma Abeta levels, confirming pharmacodynamic activity of GSI-953 in humans.
authors: Wyeth Research, Departments of Discovery Neuroscience, Princeton, New Jersey 08543, USA.
authors: Robert L
authors: RL
authors: Martone
authors: Hua
authors: H
authors: Zhou
authors: Kevin
authors: K
authors: Atchison
authors: Thomas
authors: T
authors: Comery
authors: Jane Z
authors: JZ
authors: Xu
authors: Xinyi
authors: X
authors: Huang
authors: Xioahai
authors: X
authors: Gong
authors: Mei
authors: M
authors: Jin
authors: Anthony
authors: A
authors: Kreft
authors: Boyd
authors: B
authors: Harrison
authors: Scott C
authors: SC
authors: Mayer
authors: Suzan
authors: S
authors: Aschmies
authors: Cathleen
authors: C
authors: Gonzales
authors: Margaret M
authors: MM
authors: Zaleska
authors: David R
authors: DR
authors: Riddell
authors: Erik
authors: E
authors: Wagner
authors: Peimin
authors: P
authors: Lu
authors: Shaiu-Ching
authors: SC
authors: Sun
authors: June
authors: J
authors: Sonnenberg-Reines
authors: Aram
authors: A
authors: Oganesian
authors: Karissa
authors: K
authors: Adkins
authors: Michael W
authors: MW
authors: Leach
authors: David W
authors: DW
authors: Clarke
authors: Donna
authors: D
authors: Huryn
authors: Magid
authors: M
authors: Abou-Gharbia
authors: Ronald
authors: R
authors: Magolda
authors: Jonathan
authors: J
authors: Bard
authors: Glen
authors: G
authors: Frick
authors: Sangeeta
authors: S
authors: Raje
authors: S Bradley
authors: SB
authors: Forlow
authors: Carrie
authors: C
authors: Balliet
authors: Michael E
authors: ME
authors: Burczynski
authors: Peter H
authors: PH
authors: Reinhart
authors: Hong I
authors: HI
authors: Wan
authors: Menelas N
authors: MN
authors: Pangalos
authors: J Steven
authors: JS
authors: Jacobsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D005239:Fear / Q000523:psychology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D013876:Thiophenes / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D055815:Young Adult
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D051880:Receptors, Notch; D013449:Sulfonamides; D013876:Thiophenes; C539549:begacestat; D053829:Amyloid Precursor Protein Secretases