Optimization of a Novel Series of TRPV4 Antagonists with In Vivo Activity in a Model of Pulmonary Edema

High-throughput screening and subsequent hit optimization identified 1-piperidinylbenzimidazoles, exemplified by compound <b>1</b>, as TRPV4 inhibitors. Lead optimization identified potent TRPV4 blocker <b>19</b>, which has good target activity and pharmacokinetic properties. Inhibitor <b>19</b> was then profiled in an in vivo rat model, demonstrating its ability to inhibit TRPV4-mediated pulmonary edema

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