title: Discovery and initial optimization of 5,5'-disubstituted aminohydantoins as potent beta-secretase (BACE1) inhibitors.
abstract: 8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket.
authors: Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States. nowakp@wyeth.com
authors: Pawel
authors: P
authors: Nowak
authors: Derek C
authors: DC
authors: Cole
authors: Ann
authors: A
authors: Aulabaugh
authors: Jonathan
authors: J
authors: Bard
authors: Rajiv
authors: R
authors: Chopra
authors: Rebecca
authors: R
authors: Cowling
authors: Kristi Y
authors: KY
authors: Fan
authors: Baihua
authors: B
authors: Hu
authors: Steve
authors: S
authors: Jacobsen
authors: Minakshi
authors: M
authors: Jani
authors: Guixan
authors: G
authors: Jin
authors: Mei-Chu
authors: MC
authors: Lo
authors: Michael S
authors: MS
authors: Malamas
authors: Eric S
authors: ES
authors: Manas
authors: Rani
authors: R
authors: Narasimhan
authors: Peter
authors: P
authors: Reinhart
authors: Albert J
authors: AJ
authors: Robichaud
authors: Joseph R
authors: JR
authors: Stock
authors: Joan
authors: J
authors: Subrath
authors: Kristine
authors: K
authors: Svenson
authors: Jim
authors: J
authors: Turner
authors: Erik
authors: E
authors: Wagner
authors: Ping
authors: P
authors: Zhou
authors: John W
authors: JW
authors: Ellingboe
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D006827:Hydantoins; D007093:Imidazoles; D053829:Amyloid Precursor Protein Secretases