ABSTRACT
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, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.
Subject(s)
Calcium Channel Blockers/pharmacology , Calcium Release Activated Calcium Channels/antagonists & inhibitors , Calcium/metabolism , Drug Discovery , Administration, Oral , Animals , Area Under Curve , Arthritis, Rheumatoid/drug therapy , Calcium Channel Blockers/pharmacokinetics , Clinical Trials, Phase I as Topic , Humans , Jurkat Cells , Male , Mice , Mice, Inbred BALB C , Rats , Rats, Inbred Lew , Structure-Activity RelationshipABSTRACT
The first "In Water" imidazolecarbonylation of amine is described. A one pot reaction of carbonylimidazolide in water with a nucleophile provides an efficient and general method for the preparation of urea, carbamates and thiocarbamates. Use of an anhydrous solvent and an inert atmosphere could be avoided. Product precipitate out from the reaction mixture and can be obtained in high purity by filtration, resulting in a simple and scalable method.
Subject(s)
Amines/chemistry , Carbamates/chemical synthesis , Imidazoles/chemistry , Thiocarbamates/chemical synthesis , Urea/analogs & derivatives , Urea/chemical synthesis , Water/chemistry , Carbamates/chemistry , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , Thiocarbamates/chemistry , Urea/chemistryABSTRACT
A new method for the oxidation of nucleoside phosphite triester into phosphate triester under nonbasic and nonaqueous conditions using NBS-DMSO in CH(3)CN has been developed. The utility of this method for solution- and solid-phase synthesis of oligonucleotide is demonstrated.
Subject(s)
Dimethyl Sulfoxide/chemistry , Oligonucleotides/chemical synthesis , Chromatography, High Pressure Liquid , Indicators and Reagents , Magnetic Resonance Spectroscopy , Oxidation-ReductionABSTRACT
The mixture of carbon tetrachloride, N-methyl morpholine (NMM), pyridine and water in acetonitrile has been exploited for the oxidation of dinucleoside H-phosphonate diesters to the corresponding phosphates. The system is found to be inert to the phosphoramidate (P-N) and the phosphorothioate (P-S) linkages and has successfully been applied to the solid phase synthesis of mixed-backbone oligonucleotides (MBOs).
