4 research outputs found
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
Comparative molecular field analysis and synthetic validation of a hydroxyamide-propofol binding and functional block of neuronal voltage-dependent sodium channels
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)Âphenyl]-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