TY - JOUR
T1 - 2,6-Difluorobenzamide derivatives as store-operated calcium channel (SOC) inhibitors
AU - Wang, Yu Shiuan
AU - Yeh, Teng Kuang
AU - Chang, Wei Chiao
AU - Liou, Jing Ping
AU - Liu, Yi Min
AU - Huang, Wan Chen
N1 - Funding Information:
This research was supported by the Ministry of Science and Technology, Taiwan (grant no. MOST 109-2320-B-038-042 ).
Funding Information:
Previous results showed that the MPT0M004 (8a) is a compound that supports anti-CRC progression. Accordingly, we next examined the pharmacokinetic parameters of MPT0M004 (8a) in the rat compared to the standard (5), and the results are shown in Table 1. The dose of standard (5) and MPT0M004 (8a) for I.V. or P.O. administration was 2 or 20 mg/kg, respectively. The half-life (T1/2) in the I.V. or the P.O. model was found to be 24 and 16 h, respectively, which indicates that MPT0M004 (8a) administered by I.V. has a longer half-life at a lower daily dose. The AUC(0-inf) of MPT0M004 (8a) has shown better than standard (5). The PK results also showed that MPT0M004 (8a) administered P.O. takes longer to reach the maximum concentration in vivo (Tmax = 6 h) and has F = 34% of oral bioavailability.This research was supported by the Ministry of Science and Technology, Taiwan (grant no. MOST 109-2320-B-038-042).
Publisher Copyright:
© 2022 Elsevier Masson SAS
PY - 2022/12/5
Y1 - 2022/12/5
N2 - The Ca2+ entry from store-operated Ca2+ channel (SOC) is involved in regulating colorectal cancer progression, such as cell migration. SOC activation is due to STIM1 translocation and interaction with Orai1 upon Ca2+ depletion in the ER. Numerous SOC inhibitors, like 2-APB, have been developed and demonstrated their inhibition effects in the preclinical stage. However, most currently used SOC inhibitors have higher cytotoxicity or opposite effects at different doses, and the drugs to target SOC in the clinic are lacking. In this study, a total of 13 difluorobenzamide compounds had been synthesized and examined the inhibitory effects on SOC with Ca2+ imaging and wound-healing migration assay. Among them, 2,6-Difluoro-N-(5-(4-fluorophenyl)pyridine-2-yl)benzamide (MPT0M004, 8a) demonstrated a prominent inhibitory ability on SOC. Furthermore, the cell proliferation assay results showed that MPT0M004 (8a) had lower cytotoxicity than 2-APB, the reference compound. In the pharmacokinetic study, MPT0M004 (8a) has a long half-life (T1/2 = 24 h) and lower daily dose administered intravenously with an oral bioavailability (F = 34%). Therefore, MPT0M004 (8a) has the potential to be a lead compound as a SOC inhibitor and further develop into a potential drug to treat colorectal cancer.
AB - The Ca2+ entry from store-operated Ca2+ channel (SOC) is involved in regulating colorectal cancer progression, such as cell migration. SOC activation is due to STIM1 translocation and interaction with Orai1 upon Ca2+ depletion in the ER. Numerous SOC inhibitors, like 2-APB, have been developed and demonstrated their inhibition effects in the preclinical stage. However, most currently used SOC inhibitors have higher cytotoxicity or opposite effects at different doses, and the drugs to target SOC in the clinic are lacking. In this study, a total of 13 difluorobenzamide compounds had been synthesized and examined the inhibitory effects on SOC with Ca2+ imaging and wound-healing migration assay. Among them, 2,6-Difluoro-N-(5-(4-fluorophenyl)pyridine-2-yl)benzamide (MPT0M004, 8a) demonstrated a prominent inhibitory ability on SOC. Furthermore, the cell proliferation assay results showed that MPT0M004 (8a) had lower cytotoxicity than 2-APB, the reference compound. In the pharmacokinetic study, MPT0M004 (8a) has a long half-life (T1/2 = 24 h) and lower daily dose administered intravenously with an oral bioavailability (F = 34%). Therefore, MPT0M004 (8a) has the potential to be a lead compound as a SOC inhibitor and further develop into a potential drug to treat colorectal cancer.
KW - Colorectal cancer (CRC)
KW - Diflurobenzamides
KW - Orai1
KW - STIM1
KW - Store-operated calcium channel (SOC) inhibitors
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U2 - 10.1016/j.ejmech.2022.114773
DO - 10.1016/j.ejmech.2022.114773
M3 - Article
C2 - 36179401
AN - SCOPUS:85139065135
SN - 0223-5234
VL - 243
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 114773
ER -