title: Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors.
abstract: Discovery of a series of pyrazolopiperidine sulfonamide based gamma-secretase inhibitors and its SAR evolution is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved in vivo efficacy.
authors.affiliation: Department of Medicinal Chemistry, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States. michael.ye@elan.com
authors.forename: Xiaocong M
authors.initials: XM
authors.lastname: Ye
authors.forename: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Jenifer
authors.initials: J
authors.lastname: Smith
authors.forename: Ying-Zi
authors.initials: YZ
authors.lastname: Xu
authors.forename: Darren
authors.initials: D
authors.lastname: Dressen
authors.forename: Albert W
authors.initials: AW
authors.lastname: Garofalo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Marugg
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Anh P
authors.initials: AP
authors.lastname: Truong
authors.forename: Jacek
authors.initials: J
authors.lastname: Jagodzinski
authors.forename: Michael
authors.initials: M
authors.lastname: Pleiss
authors.forename: Hongbin
authors.initials: H
authors.lastname: Zhang
authors.forename: Erich
authors.initials: E
authors.lastname: Goldbach
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Brigham
authors.forename: Michael
authors.initials: M
authors.lastname: Bova
authors.forename: Guriqbal S
authors.initials: GS
authors.lastname: Basi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D010880:Piperidines; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases