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 (T_1/2 = 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.

01 Mar 2022·Journal of Inorganic BiochemistryQ2 · BIOLOGY

Characterization of copper(II) specific pyridine containing ligands: Potential metallophores for Alzheimer's disease therapy

Q2 · BIOLOGY

Article

Author: Kiss, Tamás ; Jakusch, Tamás ; Hassoon, Azza A

Two amide group containing pyridine derivatives, N-(pyridin-2-ylmethyl)picolinamide (PMPA) and N-(pyridin-2-ylmethyl)-2-((pyridin-2-ylmethyl)amino)acetamide (DPMGA), have been investigated as potential metallo-phores in the therapy of Alzheimer's disease. Their complex formation with Cu(II) and Zn(II) were characterized in details. Unexpectedly not only the Cu(II) but also the Zn(II) was able to induce deprotonation of the amide-NH, however, it occurred only at higher pH or at higher metal ion concentrations than the biological conditions. At μM concentration level mono complexes (MLH_-₁) dominate with both ligands. Direct fluorescence and reactive oxygen species (ROS) producing measurements prove that both ligands are able to remove Cu(II) from its amyloid-β complexes (CuAβ). Correlation was also established between the conditional stability constant of the Cu(II) complexes with different ligands and their ability of inhibition of ROS production by CuAβ.

01 May 2010·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Discovery of 2-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-5-(5-fluoropyrimidin-2-yl)benzamide as a potent and CNS penetrable P2X7 receptor antagonist

Q4 · MEDICINE

Article

Author: Phillion, Dennis P. ; Naing, Win ; Pierce, Betsy ; Grapperhaus, Margaret L. ; Chen, Xiangyang

Focused SAR studies were carried out around 5-heteroaryl and 1-amide portions of the 2-chlorobenzamide scaffold, resulting in the discovery of a potent, metabolically stable and centrally penetrable antagonist against P2X(7) receptor.

100 Deals associated with BMS-605541

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Indication	Highest Phase	Country/Location	Organization	Date
Colonic Cancer	Preclinical	US	Bristol Myers Squibb Co.	26 May 2006
Lung Cancer	Preclinical	US	Bristol Myers Squibb Co.	26 May 2006

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