Core refinement toward permeable β-secretase (BACE-1) inhibitors with low hERG activity

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Drug Discovery

Background:

• Alzheimer's disease is a progressive neurodegenerative disorder characterized by amyloid-beta plaques, for which beta-secretase 1 (BACE-1) is a key therapeutic target.
• Developing effective BACE-1 inhibitors requires careful optimization of properties like target affinity, brain permeability, and safety (hERG activity).

Purpose of the Study:

• To design and synthesize novel, diverse compounds utilizing cyclic amidine and guanidine cores as potential inhibitors of BACE-1.
• To explore structure-activity relationships (SAR) and in vivo properties of these novel compounds for Alzheimer's disease treatment.

Main Methods:

• Iterative design incorporating predictive models for target affinity, brain permeability, and hERG activity.
• Extensive synthesis of compounds based on cyclic amidine and guanidine cores, prioritizing drug-like properties over initial synthesis ease.
• In vitro biochemical and cellular assays to determine compound potencies and physicochemical properties.
• X-ray crystallography to elucidate binding modes of amidine compounds in the BACE-1 active site.
• In vivo studies to assess brain exposure levels of promising drug candidates.

Main Results:

• Successful synthesis of diverse compounds based on cyclic amidine and guanidine scaffolds.
• Identification of BACE-1 inhibitors with cellular potencies ranging from 3 μM to 32 nM.
• Four crystal structures revealed detailed binding interactions within the BACE-1 active site.
• Demonstrated in vivo brain exposure for four selected compounds.
• Established structure-activity relationships indicating the significance of the core structure for compound profiles.

Conclusions:

• Novel cyclic amidine and guanidine derivatives show promise as BACE-1 inhibitors for Alzheimer's disease.
• The core scaffold significantly influences the overall pharmacological profile, including potency and brain penetration.
• This study provides valuable insights into the design of effective BACE-1 inhibitors for potential therapeutic applications.