AI Article Synopsis
- BMP1 inhibition is being researched as a treatment for fibrosis since BMP1 is crucial for converting pro-collagen to collagen.
- A new class of reverse hydroxamate BMP1 inhibitors was developed, with unique binding properties that allow for selective targeting of metalloproteases.
- To mitigate drug-drug interaction risks associated with irreversible inhibition of cytochrome P450 3A4, adjustments were made to the compound for subcutaneous delivery instead of oral use.
Article Abstract
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 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047045 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.8b00173 | DOI Listing |
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