title: Pyridinyl aminohydantoins as small molecule BACE1 inhibitors.
abstract: A novel class of pyridinyl aminohydantoins was designed and prepared as highly potent BACE1 inhibitors. Compound (S)-4g showed excellent potency with IC(50) of 20 nM for BACE1. X-ray crystallography indicated that the interaction between pyridine nitrogen and the tryptophan Trp76 was a key feature in the S2' region of the enzyme that contributed to increased potency.
authors.affiliation: Department of Chemical Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, United States. zhoupb31@gmail.com
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Andrea
authors.initials: A
authors.lastname: Olland
authors.forename: Yun
authors.initials: Y
authors.lastname: Hu
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Magolda
authors.forename: Menelas
authors.initials: M
authors.lastname: Pangalos
authors.forename: Peter H
authors.initials: PH
authors.lastname: Reinhart
authors.forename: M James
authors.initials: MJ
authors.lastname: Turner
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bard
authors.forename: Michael S
authors.initials: MS
authors.lastname: Malamas
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006827:Hydantoins; D011725:Pyridines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human