{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Brodney MA"],"funding":["National Institute of General Medical Sciences","NIGMS NIH HHS"],"pagination":["3223-52"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4415909"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["58(7)"],"pubmed_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."],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors."],"pmcid":["PMC4415909"],"funding_grant_id":["R01 GM031001","R01GM031001"],"pubmed_authors":["Johnson EF","Robshaw AE","Beck EM","Murray JC","Hou X","Riddell D","Lira R","Atchison K","Butler CR","Henegar K","Dutra J","Bundesmann MW","Pandit J","Buzon L","O'Neill BT","Brodney MA","Mikochik P","Ogilvie K","Fan Y","Price L","Barreiro G","Doran SD","Nolan CE","Rogers BN","Martinez-Alsina L","Zhang Y","Yu A","LaChapelle E","Gonzales C","Parris K","Sakya SM"],"additional_accession":[]},"is_claimable":false,"name":"Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.","description":"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.","dates":{"release":"2015-01-01T00:00:00Z","publication":"2015 Apr","modification":"2026-04-16T17:14:48.028Z","creation":"2019-03-27T01:50:48Z"},"accession":"S-EPMC4415909","cross_references":{"pubmed":["25781223"],"doi":["10.1021/acs.jmedchem.5b00191"]}}