title: Discovery of isonicotinamide derived beta-secretase inhibitors: in vivo reduction of beta-amyloid.
abstract: beta-Secretase inhibition offers an exciting opportunity for therapeutic intervention in the progression of Alzheimer's disease. A series of isonicotinamides derived from traditional aspartyl protease transition state isostere inhibitors has been optimized to yield low nanomolar inhibitors with sufficient penetration across the blood-brain barrier to demonstrate beta-amyloid lowering in a murine model.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Stanton
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.forename: Alison R
authors.initials: AR
authors.lastname: Gregro
authors.forename: Melissa
authors.initials: M
authors.lastname: Steinbeiser
authors.forename: Philippe
authors.initials: P
authors.lastname: Nantermet
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Eric A
authors.initials: EA
authors.lastname: Price
authors.forename: Guoxin
authors.initials: G
authors.lastname: Wu
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Crouthamel
authors.forename: Joan
authors.initials: J
authors.lastname: Ellis
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Amy S
authors.initials: AS
authors.lastname: Espeseth
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Shi
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Beth
authors.initials: B
authors.lastname: Pietrak
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Harold
authors.initials: H
authors.lastname: Selnick
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007539:Isonicotinic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; D007539:Isonicotinic Acids; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases