title: Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors.
abstract: Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50=8nM) was made from a weak μM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed.
authors.affiliation: Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA. ying_zi_xu@yahoo.com
authors.forename: Ying-Zi
authors.initials: YZ
authors.lastname: Xu
authors.forename: Shendong
authors.initials: S
authors.lastname: Yuan
authors.forename: Simeon
authors.initials: S
authors.lastname: Bowers
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: Wayman
authors.initials: W
authors.lastname: Chan
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Yong L
authors.initials: YL
authors.lastname: Zhu
authors.forename: Paul
authors.initials: P
authors.lastname: Beroza
authors.forename: Hu
authors.initials: H
authors.lastname: Pan
authors.forename: Eric
authors.initials: E
authors.lastname: Brecht
authors.forename: Nanhua
authors.initials: N
authors.lastname: Yao
authors.forename: Julie
authors.initials: J
authors.lastname: Lougheed
authors.forename: Jiangli
authors.initials: J
authors.lastname: Yan
authors.forename: Danny
authors.initials: D
authors.lastname: Tam
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ren
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bova
authors.forename: Dean R
authors.initials: DR
authors.lastname: Artis
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C109853:G 1617; D007546:Isoquinolines; D011480:Protease Inhibitors; D013876:Thiophenes; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human