title: Aminoethylenes: a tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE-1.
abstract: A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.
authors.affiliation: Departments of Chemistry, Biochemistry, and Structural Biology, Sunesis Pharmaceuticals Incorporated, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA. wenjin@sunesis.com
authors.forename: Wenjin
authors.initials: W
authors.lastname: Yang
authors.forename: Wanli
authors.initials: W
authors.lastname: Lu
authors.forename: Yafan
authors.initials: Y
authors.lastname: Lu
authors.forename: Min
authors.initials: M
authors.lastname: Zhong
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.forename: Anila E
authors.initials: AE
authors.lastname: Thomas
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Wilkinson
authors.forename: Raymond V
authors.initials: RV
authors.lastname: Fucini
authors.forename: Melissa
authors.initials: M
authors.lastname: Lam
authors.forename: Mike
authors.initials: M
authors.lastname: Randal
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Shi
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Jacobs
authors.forename: Robert S
authors.initials: RS
authors.lastname: McDowell
authors.forename: Eric M
authors.initials: EM
authors.lastname: Gordon
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Ballinger
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010450:Endopeptidases / Q000737:chemistry*; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D005021:Ethylamines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human