Figure 1. Chemical Structure of RyR Stabilizers and
Concentration-Time Profiles in Mice Following a Single Oral Bolus of
MP-010 or MP-001 at a Dose of 30 mg/kg.
A ) Chemical structures of FKBP12 ligands MP-001, MP-002 and
MP-010. Compound MP-001 restored cytosolic calcium homeostasis in
myotubes but show limited BBB permeability (See Fig. 1A-C). Modification
to MP-002 improved BBB permeability, although the compound displayed too
short serum half-time for systemic administration. Finally, the chemical
incorporation of the sulfoxide function into MP-010 provided favorable
pharmacokinetic parameters for development.
B,C,D ) Control mice were administered a single dose of MP-010
or MP-001 at 30 mg/kg by oral gavage, and their concentrations were
assessed at 2, 4, 6, and 18 h post-dosing in the plasma (B ),
skeletal muscle (C ), and brain (D ).
D ) The calculated mean brain-to-serum (Cb:Cs) ratios were
significantly higher for MP-010 than MP-001 and exhibited values above
the threshold determining penetrability to the brain (Cb:Cs
> 0.04, dashed line).
The presented concentrations and values are the mean ± S.E.M. (n=3).
*p< 0.05 vs. MP-001-treated mice.