TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury

We describe a method of implementing the axisymmetric evolution of general-relativistic hydrodynamics and magnetohydrodynamics through modification of a multipatch grid scheme. In order to ease the computational requirements required to evolve the post-merger phase of systems involving binary compact massive objects in numerical relativity, it is often beneficial to take advantage of these system's tendency to rapidly settle into states that are nearly axisymmetric, allowing for 2D evolution of secular timescales. We implement this scheme in the spectral Einstein code and show the results of application of this method to four test systems including viscosity, magnetic fields, and neutrino radiation transport. Our results show that this method can be used to quickly allow already existing 3D infrastructure that makes use of local coordinate system transformations to be made to run in axisymmetric 2D with the flexible grid creation capabilities of multipatch methods. Our code tests include a simple model of a binary neutron star postmerger remnant, for which we confirm the formation of a massive torus which is a promising source of post-merger ejecta

Discovery of GSK2193874: An Orally Active, Potent, and Selective Blocker of Transient Receptor Potential Vanilloid 4

Transient Receptor Potential Vanilloid 4 (TRPV4) is a member of the Transient Receptor Potential (TRP) superfamily of cation channels. TRPV4 is expressed in the vascular endothelium in the lung and regulates the integrity of the alveolar septal barrier. Increased pulmonary vascular pressure evokes TRPV4-dependent pulmonary edema, and therefore, inhibition of TRPV4 represents a novel approach for the treatment of pulmonary edema associated with conditions such as congestive heart failure. Herein we report the discovery of an orally active, potent, and selective TRPV4 blocker, 3-(1,4′-bipiperidin-1′-ylmethyl)-7-bromo-<i>N</i>-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)­phenyl]-4-quinolinecarboxamide (GSK2193874, <b>28</b>) after addressing an unexpected off-target cardiovascular liability observed from <i>in vivo</i> studies. GSK2193874 is a selective tool for elucidating TRPV4 biology both <i>in vitro</i> and <i>in vivo</i>

Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1

Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral <i>in vivo</i> tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug–drug interactions was managed by optimizing the series for subcutaneous injection

Discovery of 6‑Phenylpyrimido[4,5‑<i>b</i>][1,4]oxazines as Potent and Selective Acyl CoA:Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors with in Vivo Efficacy in Rodents

The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido­[4,5-<i>b</i>]­[1,4]­oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid <b>1</b>, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of <b>1</b> was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane <b>42</b>, which displayed significantly improved DGAT1 inhibition compared to <b>1</b>. Spiroindane <b>42</b> was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies