Discovery of a Novel Potent and Selective Calcium Release-Activated Calcium Channel Inhibitor: 2,6-Difluoro--(2'-methyl-3'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-4-yl)benzamide. Structure-Activity Relationship and Preclinical Characterization.

The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, and .

A surface exposed O-linked galactose residue destabilises the structure of a folded helix-loop-helix dimer.

A 42-residue glycopeptide Tn-15 and the corresponding reference polypeptide Thr-15 were designed and synthesized to provide a model system for the study of how glycosylation affects the stability of a molten globule-like protein. Tn-15 and Thr-15 fold into hairpin helix-loop-helix motifs that dimerise to form four-helix bundles and the only difference between the sequences is that Tn-15 carries an O-linked N-acetylgalactosamine residue at the side chain of threonine-15 whereas the sequence Thr-15 is unglycosylated. An analysis of the mean residue ellipticities at 222 nm of the two polypeptides and of the alpha-H chemical shift deviations from random coil values showed that glycosylation reduced the helical content of the polypeptides and increased the dissociation constant of the helix-loop-helix dimer to form monomers.

Synthesis of Some Copper(II)-Chelating (Dialkylamino)pyridine Amphiphiles and Evaluation of Their Esterolytic Capacities in Cationic Micellar Media.

Three new (dialkylamino)pyridine (DAAP)-based ligand amphiphiles 3-5 have been synthesized. All of the compounds possess a metal ion binding subunit in the form of a 2,6-disubstituted DAAP moiety. In addition, at least one ortho-CH(2)OH substituent is present in all the ligands.