title: 8-Tetrahydropyran-2-yl chromans: highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors.
abstract: A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aβ1-40 at 60 mg/kg (PO).
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Allen A
authors.initials: AA
authors.lastname: Thomas
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hunt
authors.forename: Brad
authors.initials: B
authors.lastname: Newhouse
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
authors.forename: Guy
authors.initials: G
authors.lastname: Vigers
authors.forename: Darin
authors.initials: D
authors.lastname: Smith
authors.forename: Susan P
authors.initials: SP
authors.lastname: Rhodes
authors.forename: Karin D
authors.initials: KD
authors.lastname: Brown
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Otten
authors.forename: Michael
authors.initials: M
authors.lastname: Burkard
authors.forename: April A
authors.initials: AA
authors.lastname: Cox
authors.forename: Mary K
authors.initials: MK
authors.lastname: Geck Do
authors.forename: Darrin
authors.initials: D
authors.lastname: Dutcher
authors.forename: Sumeet
authors.initials: S
authors.lastname: Rana
authors.forename: Robert K
authors.initials: RK
authors.lastname: DeLisle
authors.forename: Kelly
authors.initials: K
authors.lastname: Regal
authors.forename: Albion D
authors.initials: AD
authors.lastname: Wright
authors.forename: Robert
authors.initials: R
authors.lastname: Groneberg
authors.forename: Jiangpeng
authors.initials: J
authors.lastname: Liao
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.forename: Michael
authors.initials: M
authors.lastname: Siu
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001921:Brain / Q000378:metabolism; D002402:Cathepsin D; D002839:Chromans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C000595480:3-((4R,4a'S,10a'R)-2-amino-4a'-methyl-3',4',4a',10a'-tetrahydro-2'H,5H-spiro(oxazole-4,10'-pyrano(3,2-b)chromen)-8'-yl)benzonitrile; D002839:Chromans; D011480:Protease Inhibitors; D013141:Spiro Compounds; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; D002402:Cathepsin D