2 research outputs found
Design, Synthesis, and Evaluation of Analogues of 3,3,3-Trifluoro-2-Hydroxy-2-Phenyl-Propionamide as Orally Available General Anesthetics
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