Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors

• Published in: Journal of medicinal chemistry Vol. 58; no. 7; pp. 3223 - 3252
• Main Authors: Brodney, Michael A, Beck, Elizabeth M, Butler, Christopher R, Barreiro, Gabriela, Johnson, Eric F, Riddell, David, Parris, Kevin, Nolan, Charles E, Fan, Ying, Atchison, Kevin, Gonzales, Cathleen, Robshaw, Ashley E, Doran, Shawn D, Bundesmann, Mark W, Buzon, Leanne, Dutra, Jason, Henegar, Kevin, LaChapelle, Erik, Hou, Xinjun, Rogers, Bruce N, Pandit, Jayvardhan, Lira, Ricardo, Martinez-Alsina, Luis, Mikochik, Peter, Murray, John C, Ogilvie, Kevin, Price, Loren, Sakya, Subas M, Yu, Aijia, Zhang, Yong, O’Neill, Brian T
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.04.2015; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: 60 APPLIED LIFE SCIENCES; Amino Acid Sequence; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - chemistry; Amyloidogenic Proteins - metabolism; Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Chemistry, Medicinal; Crystallography, X-Ray; Cytochrome P-450 CYP2D6 - chemistry; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Drug Design; Drug Interactions; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Ether-A-Go-Go Potassium Channels - metabolism; Humans; Inhibitory Concentration 50; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Life Sciences & Biomedicine; Male; Mice, Inbred Strains; Models, Molecular; Molecular Sequence Data; Pharmacology & Pharmacy; Protease Inhibitors - administration & dosage; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacokinetics; Protease Inhibitors - pharmacology; Pyrazoles - chemistry; Science & Technology; Structure-Activity Relationship; MEDICINAL CHEMISTRY; MOLECULAR-GENETICS; HERG; REAGENTS; ALZHEIMERS-DISEASE; AMYLOID-BETA; CRYSTAL-STRUCTURE; FLUORINATION; DISCOVERY; CYTOCHROME-P450 2D6
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00191

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.