Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors

Journal of Medicinal Chemistry
Michael A BrodneyBrian T O'Neill

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.

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Citations

Feb 26, 2016·The Journal of Physical Chemistry Letters·Christopher R EllisJana Shen
Jun 9, 2016·Trends in Pharmacological Sciences·F Peter GuengerichMartin Egli
Oct 8, 2016·Molecular Neurodegeneration·Martina PigoniStefan F Lichtenthaler
Dec 21, 2016·Journal of Medicinal Chemistry·Christopher R ButlerMichael A Brodney
Apr 4, 2017·Journal of Computational Chemistry·Christopher R EllisJana Shen
May 5, 2016·Organic & Biomolecular Chemistry·Rachel K ChambersBrad E Sleebs
Jul 28, 2017·Journal of Medicinal Chemistry·Federica PratiAndrea Cavalli
Jun 9, 2018·Frontiers in Chemistry·Judite R M CoimbraJorge A R Salvador
Aug 16, 2017·Scientific Reports·Johannes HochleitnerDaniela Schuster
Aug 19, 2017·Expert Opinion on Drug Discovery·Li Di
Apr 3, 2018·Expert Opinion on Drug Discovery·Ramón Cacabelos
Jan 19, 2021·ACS Chemical Neuroscience·Elena LenciAndrea Trabocchi
Oct 3, 2020·Expert Opinion on Therapeutic Patents·Frederik RomboutsHarrie J M Gijsen
Feb 23, 2021·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Haizhou ZhuSwati S More
Feb 19, 2021·ChemMedChem·Xiaoxiao ZhangWeihua Li
Dec 12, 2018·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Akihiro TakanoChrister Halldin
Nov 3, 2017·The Journal of Organic Chemistry·Luis A Martinez-AlsinaBrian T O'Neill
Nov 13, 2019·Journal of Chemical Information and Modeling·Nootcharin WasukanRawiwan Maniratanachote
Aug 22, 2018·Journal of Chemical Information and Modeling·André FischerMartin Smieško
Jul 7, 2021·SLAS Discovery·Joshua R BornSamarjit Patnaik

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Methods Mentioned

BETA
transgenic
fluorescence
X-ray
NMR
Assay
ELISA
enzyme-linked immunosorbent assay
equilibrium dialysis
light scattering
column chromatography

Software Mentioned

Coot
REFMAC
AB Sciex analyst
XDS
Sophion Qpatch assay
Phenix
Analyst
Qpatch

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