Enantioselective synthesis and selective functionalization of 4-aminotetrahydroquinolines as novel GLP-1 secretagogues.

Polysubstituted tetrahydroquinolines were obtained in moderate to high yields (28% to 92%) and enantiomeric ratios (er 89:11 to 99:1) by a three-component Povarov reaction using a chiral phosphoric acid catalyst. Significantly, post-Povarov functional group interconversions allowed a rapid access to a library of 36 enantioenriched 4-aminotetrahydroquinoline derivatives featuring five points of diversity. Selected analogs were assayed for their ability to function as glucagon-like peptide-1 (GLP-1) secretagogues.

An uncharged oxetanyl sulfoxide as a covalent modifier for improving aqueous solubility.

Low aqueous solubility is a common challenge in drug discovery and development and can lead to inconclusive biological assay results. Attaching small, polar groups that do not interfere with the bioactivity of the pharmacophore often improves solubility, but there is a dearth of viable neutral moieties available for this purpose. We have modified several poorly soluble drugs or drug candidates with the oxetanyl sulfoxide moiety of the DMSO analog MMS-350 and noted in most cases a moderate to large improvement of aqueous solubility. Furthermore, the membrane permeability of a test sample was enhanced compared to the parent compound.