Figure 1.

Characterization of β-hex-targeted pharmacological chaperone OT1001. OT1001 is a potent and specific inhibitor of β-hex demonstrating target engagement at sub-micromolar concentrations (a). OT1001 treatment of healthy human derived fibroblasts with OT1001 (95–780 nM) for 5 days resulted in a dose-dependent increase in wild-type total β-hex levels up to threefold (b). Five-week-old male C57BL/J6 mice were given a single 100 mg kg⁻¹ dose of the β-hex-targeted pharmacological chaperone OT1001; plasma (c) and brain (d) OT1001 profiles. A 100 mg kg⁻¹ dose of OT1001 crossed the blood–brain barrier and reached levels in the brain that are predicted to be sufficient to bind and increase β-hex levels (>342 nM) and dropped below K_i (253 nM at pH 5) levels for β-hex within 16 h (n=5 mice per time point). Five-week-old male C57BL/J6 mice were orally gavaged either with vehicle, 30, 100 or 300 mg kg⁻¹ of the β-hex-targeted pharmacological chaperone OT1001 daily up to 14 days. Whole brain β-hex A&S (e) and β-hex B (f) activity (n=5 mice per time point). Data expressed as mean±s.e.m. β-hex, β-hexosaminidase.