title: Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.
abstract: The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.
authors: Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA. simeongbowers@gmail.com
authors: Simeon
authors: S
authors: Bowers
authors: Ying-zi
authors: YZ
authors: Xu
authors: Shendong
authors: S
authors: Yuan
authors: Gary D
authors: GD
authors: Probst
authors: Roy K
authors: RK
authors: Hom
authors: Wayman
authors: W
authors: Chan
authors: Andrei W
authors: AW
authors: Konradi
authors: Hing L
authors: HL
authors: Sham
authors: Yong L
authors: YL
authors: Zhu
authors: Paul
authors: P
authors: Beroza
authors: Hu
authors: H
authors: Pan
authors: Eric
authors: E
authors: Brecht
authors: Nanhua
authors: N
authors: Yao
authors: Julie
authors: J
authors: Lougheed
authors: Danny
authors: D
authors: Tam
authors: Zhao
authors: Z
authors: Ren
authors: Lany
authors: L
authors: Ruslim
authors: Michael P
authors: MP
authors: Bova
authors: Dean R
authors: DR
authors: Artis
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001224:Aspartic Acid / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002384:Catalysis; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C109853:G 1617; D007546:Isoquinolines; D011480:Protease Inhibitors; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human