ABSTRACT
An efficient method is described to tritiate spiperone at high specific activity.
Subject(s)
Spiperone/chemistry , Tritium/chemistry , Catalysis , Magnetic Resonance Spectroscopy/methods , Radioligand Assay , Spectrometry, Mass, Electrospray IonizationABSTRACT
As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure-activity relationships of this class of molecules were explored. Compound 1k, with EC(50) of 270 nM and GI(50) of 229 nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound 1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50 mpk, bid.
Subject(s)
Amides/chemistry , Amides/pharmacology , Apoptosis/drug effects , Oxazoles/chemistry , Oxazoles/pharmacology , Amides/chemical synthesis , Animals , Cell Line, Tumor , Female , Humans , Mice , Molecular Structure , Oxazoles/chemical synthesis , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
The metabolites of the tryptase inhibitor CRA-9249 were identified after exposure to liver microsomes. CRA-9249 was found to be degraded rapidly in liver microsomes from rabbit, dog, cynomolgus monkey, and human, and less rapidly in microsomes from rat. The key metabolites included cleavage of an aryl ether, in addition to an unexpected hydroxylation of the amide side chain adjacent to the amide nitrogen. The chemical structures of both metabolites were confirmed by synthesis and comparison to material isolated from the liver microsomes. Several suspected hydroxylated metabolites were also synthesized and analyzed as part of the structure identification process.
Subject(s)
Benzimidazoles/metabolism , Enzyme Inhibitors/metabolism , Serine Endopeptidases/drug effects , Animals , Chromatography, High Pressure Liquid , Dogs , Hydroxylation , Macaca fascicularis , Magnetic Resonance Spectroscopy , Rats , TryptasesABSTRACT
Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn(2+)-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn(2+) conditions (K(i)=27nM). This compound (46) binds also to NS3/NS4A in a Zn(2+) independent fashion (K(i)=1microM). The SAR of this class of compounds under Zn(2+) conditions is highly divergent compared to the SAR in the absence of Zn(2+), suggesting two distinct binding modes.
