title: Discovery of 7-tetrahydropyran-2-yl chromans: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid β-protein (Aβ) in the central nervous system.
abstract: In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2' sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aβ1-40 production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (Cfree,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of Aβ1-40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.
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: Matthew
authors.initials: M
authors.lastname: Volgraf
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: Douglas
authors.initials: D
authors.lastname: Sammond
authors.forename: Tony P
authors.initials: TP
authors.lastname: Tang
authors.forename: Susan P
authors.initials: SP
authors.lastname: Rhodes
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Metcalf
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 Geck
authors.initials: MK
authors.lastname: 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: 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
authors.forename: Indrani W
authors.initials: IW
authors.lastname: Gunawardana
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002839:Chromans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011714:Pyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D002839:Chromans; D011714:Pyrans; D013141:Spiro Compounds; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human