title: Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: from hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species.
abstract: A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey.
authors.affiliation: Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA. hunt@arraybiopharma.com
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hunt
authors.forename: Adam W
authors.initials: AW
authors.lastname: Cook
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Clark
authors.forename: Guy
authors.initials: G
authors.lastname: Vigers
authors.forename: Darin
authors.initials: D
authors.lastname: Smith
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Metcalf
authors.forename: Indrani W
authors.initials: IW
authors.lastname: Gunawardana
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: Allen A
authors.initials: AA
authors.lastname: Thomas
authors.forename: Sumeet
authors.initials: S
authors.lastname: Rana
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Kallan
authors.forename: Robert K
authors.initials: RK
authors.lastname: DeLisle
authors.forename: James P
authors.initials: JP
authors.lastname: Rizzi
authors.forename: Kelly
authors.initials: K
authors.lastname: Regal
authors.forename: Douglas
authors.initials: D
authors.lastname: Sammond
authors.forename: Robert
authors.initials: R
authors.lastname: Groneberg
authors.forename: Michael
authors.initials: M
authors.lastname: Siu
authors.forename: Hans
authors.initials: H
authors.lastname: Purkey
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
authors.forename: Allison
authors.initials: A
authors.lastname: Marlow
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
authors.forename: Tony P
authors.initials: TP
authors.lastname: Tang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002839:Chromans / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D002839:Chromans; D006827:Hydantoins; D011480:Protease Inhibitors; D013141:Spiro Compounds; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human