Novel Pyridazinone Inhibitors for Vascular Adhesion Protein‑1 (VAP-1): Old Target–New Inhibition Mode

Vascular adhesion protein-1 (VAP-1) is a primary amine oxidase and a drug target for inflammatory and vascular diseases. Despite extensive attempts to develop potent, specific, and reversible inhibitors of its enzyme activity, the task has proven challenging. Here we report the synthesis, inhibitory activity, and molecular binding mode of novel pyridazinone inhibitors, which show specificity for VAP-1 over monoamine and diamine oxidases. The crystal structures of three inhibitor–VAP-1 complexes show that these compounds bind reversibly into a unique binding site in the active site channel. Although they are good inhibitors of human VAP-1, they do not inhibit rodent VAP-1 well. To investigate this further, we used homology modeling and structural comparison to identify amino acid differences, which explain the species-specific binding properties. Our results prove the potency and specificity of these new inhibitors, and the detailed characterization of their binding mode is of importance for further development of VAP-1 inhibitors

HATS-71b: A Giant Planet Transiting an M3 Dwarf Star in TESS Sector 1

We report the discovery of HATS-71b, a transiting gas giant planet on a P = 3.7955 day orbit around aG = 15.35 mag M3 dwarf star. HATS-71 is the coolest Mdwarf star known to host a hot Jupiter. The loss of light during transits is 4.7%, more than in any other confirmed transiting planet system. The planet was identified as a candidate by the ground-based HATSouth transit survey. It was confirmed using ground-based photometry, spectroscopy, and imaging, as well as spacebased photometry from the NASA Transiting Exoplanet Survey Satellite mission (TIC 234523599). Combining all of these data, and utilizing Gaia.DR2, we find that the planet has a radius of 1.024 +/- 0.018 R-J and mass of 0.37 +/- 0.24 M-J (95% confidence upper limit of <0.80 M-J), while the star has a mass of 0.4861 +/- 0.0060 M-circle dot and a radius of 0.4783 +/- 0.0060 R-circle dot