Table 1. Pharmacokinetic parameters after oral compound administration to mice
GDC-0449
SKLB-C2209
SKLB-C2210
SKLB-C2211
Dose (mg/kg)
tmax (h)
5
5
5
5
1
1
1
1
t1/2 (h)
5.617
854
2.556
972.3
6106.538
6113.538
2.82
8.547
Cmax (ng/mL)
AUC0→t (μg/L*h)
AUC0→∞ (μg/L*h)
1606.7
6284.838
8290.712
1870
4049.8
7657.678
6511.863
17147.309
prepared from the original material 5a, which was deuterated
using a Pd/C-H2-D2O system, details are described in Supporting
Information.
Fig 4. Mean plasma concentration of 5mg/kg Vismodegib
analogs after oral administration in mice (n=3/group)
SKLB-C2211) in female CD-1 mouse were performed to
evaluate the alteration of blood circulation behaviors by
deuterium replacement at metabolically active sites of
Vismodegib. (Fig. 4) Vismodegib and its analogs were
suspended in vehicle (0.5% methyl cellulose with 0.2% Tween
80 in distilled water) and the suspension was administered orally
to the mice within a day of preparation with dose of 5 mg/kg.
Blood samples were taken at 0.25, 0.5, 1.0, 3.0, 6.0 and 24 h, and
drug plasma concentration were quantified by LC-MS/MS. As
shown in Table 1, deuterated compounds generally exhibited
better PK properties as compared to their prototype Vismodegib
at the same dose. Among all deuterated compounds, SKLB-
C2211 displayed the best than others. More specifically, SKLB-
C2211 exhibited an almost 2.24-fold increase in AUC0→∞
(μg/L*h) when compared with Vismodegib (17147.309 vs.
7657.678). Meanwhile, the half-time (t1/2) of SKLB-C2211 was
also increased to 8.547 hours by comparison with Vismodegib
(5.617 hours), indicating that SKLB-C2211 acted prolonged
blood circulation time and longer duration of action. In addition,
its peak concentration Cmax (1870 ng/mL) was observed higher
than Vismodegib (854 ng/mL), which suggested the dosage of
SKLB-C2211 may be decreased when used in clinic. By contrast,
the similar peak time (tmax) indicated that SKLB-C2211 did not
change the time of taking effect. These results implied that
deuterated compound SKLB-C2211 successfully improved the
Deuterium-labeled analogs SKLB-C2209, SKLB-C2210, and
SKLB-C2211 were synthesized according to Scheme 3.
Compound 8 was first transformed into 9 via reaction with
thionyl chloride followed by an acylation reaction using
compound 3 or 4. The target compounds were obtained via Still
Coupling reaction using 10a / 10b with 7a/ 7b.
The in vivo pharmacokinetic profile studies of Vismodegib
and its deuterated analogues (SKLB-C2209, SKLB-C2210 and
blood circulation behavior compared to its prototype
Vismodegib, and had the potential to be a long-acting inhibitor
against Hh pathway with decreased dosage. These characters are
important for clinical use because lowered dosage administration
can significantly improve the compliance of patients and reduce
side effects.
3. Ruiz-Gómez, A.; Molnar, C.; Holguín, H.; Mayor, F.; de Celis, J. F.
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In conclusion, compound SKLB-C2211 with deuterium-for-
hydrogen replacement in a metabolically active site significantly
exhibited better pharmacokinetics profiles as compared to its
prototype Vismodegib at the same dose and had a better plasma
concentration which could prolong its half-life and improve the
potency with a lower dosage. Thus, SKLB-C2211 may be a novel
long-acting inhibitor of Hh signaling pathway.
13. LoRusso, P. M.; Rudin, C. M.; Borad, M. J.; Vernillet, L.;
Darbonne, W. C.; Mackey, H.; Dimartino, J. F.; de Sauvage, F.;
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Acknowledgments
This work was supported by the National Natural Science
Foundation of China (No.81472418).
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