In Search of Selectivity in Inhibition of ADAM10

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Neuroscience

Background:

• ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) is a key target for drug discovery in various human diseases.
• Previous reports identified (6S,7S)-N-hydroxy-5-methyl-6-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)-5-azaspiro[2.5]octane-7-carboxamide (compound 1) as a selective ADAM10 inhibitor.

Purpose of the Study:

• To re-evaluate the inhibitory potential and selectivity of compound 1 against ADAM10.
• To identify and characterize alternative selective ADAM10 inhibitors for therapeutic and research applications.

Main Methods:

• Synthesis and in vitro biochemical assays to assess the potency and selectivity of compound 1 against ADAM10.
• Structure-based computational analysis to elucidate the mechanism of ADAM10 inhibition.
• Synthesis and comprehensive enzymatic profiling of compound 2, a novel candidate inhibitor.
• Pharmacokinetic studies of compound 2 in mice, including blood-brain barrier penetration assessment.

Main Results:

• Compound 1 was found to lack both potency and selectivity in inhibiting ADAM10.
• Computational modeling supported the experimental findings, excluding compound 1 as an ADAM10 inhibitor.
• Compound 2 emerged as a potent and selective ADAM10 inhibitor based on computational analysis and experimental validation.
• Compound 2 demonstrated favorable pharmacokinetic properties, including significant blood-brain barrier penetration in mice.

Conclusions:

• The initial assessment of compound 1 as an ADAM10 inhibitor was inaccurate.
• Compound 2 represents a promising selective ADAM10 inhibitor with potential utility in neurological disease research.
• Further investigation of compound 2 may elucidate the role of ADAM10 in neurological disorders and support drug development.