Discovery and Optimization of Tetrahydroisoquinoline Derivatives To Enhance Lysosome Biogenesis as Preclinical Candidates for the Treatment of Alzheimer’s Disease

More
than 55 million individuals are suffering from Alzheimer’s
disease (AD), while the effective therapeutic strategies remain elusive.
Our previous study identified a lysosome-enhancing lead compound LH2–051 with a tetrahydroisoquinoline scaffold through
a novel dopamine transporter-cyclin-dependent kinase 9-transcription
factor EB (DAT-CDK9-TFEB) regulation mechanism to promote TFEB activation
and lysosome biogenesis. Here, we launched a comprehensive structure–activity
relationship study for LH2–051, and 47 new derivatives
were designed and synthesized, in which several compounds exhibited
remarkable lysosome-enhancing activities. Notably, compounds 37 and 45 exhibited more favorable TFEB activation
and lysosome biogenesis capabilities, good safety profiles, and excellent
pharmacokinetic profiles with high brain penetration. Further investigations
demonstrated that both compounds significantly enhance the clearance
of Aβ aggregates and ameliorate the impairment of learning,
memory, and cognition in APP/PS1 mice. Overall, these results indicated
that compounds 37 and 45 are promising preclinical
drug candidates for the treatment of AD.