title: Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.
abstract: In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brodney
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Beck
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Butler
authors.forename: Gabriela
authors.initials: G
authors.lastname: Barreiro
authors.affiliation: #The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92024, United States.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Riddell
authors.forename: Kevin
authors.initials: K
authors.lastname: Parris
authors.forename: Charles E
authors.initials: CE
authors.lastname: Nolan
authors.affiliation: #The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92024, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
authors.forename: Kevin
authors.initials: K
authors.lastname: Atchison
authors.forename: Cathleen
authors.initials: C
authors.lastname: Gonzales
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Robshaw
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Doran
authors.forename: Mark W
authors.initials: MW
authors.lastname: Bundesmann
authors.forename: Leanne
authors.initials: L
authors.lastname: Buzon
authors.forename: Jason
authors.initials: J
authors.lastname: Dutra
authors.forename: Kevin
authors.initials: K
authors.lastname: Henegar
authors.forename: Erik
authors.initials: E
authors.lastname: LaChapelle
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Rogers
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lira
authors.forename: Luis
authors.initials: L
authors.lastname: Martinez-Alsina
authors.forename: Peter
authors.initials: P
authors.lastname: Mikochik
authors.forename: John C
authors.initials: JC
authors.lastname: Murray
authors.forename: Kevin
authors.initials: K
authors.lastname: Ogilvie
authors.forename: Loren
authors.initials: L
authors.lastname: Price
authors.forename: Subas M
authors.initials: SM
authors.lastname: Sakya
authors.affiliation: ∇WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Aijia
authors.initials: A
authors.lastname: Yu
authors.affiliation: ∇WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D058227:Amyloidogenic Proteins / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D004347:Drug Interactions; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D058227:Amyloidogenic Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D011480:Protease Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D019389:Cytochrome P-450 CYP2D6; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human