Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1 [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 547.2 Organic chemical reactions formerly 547.139
• Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2018
• Mô tả vật lý: Size: p. 736-740 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260237
• Chủ đề: 1. 37 inorganic, organic, physical, and analytical chemistry; 2. 60 applied life sciences; 3. Bmp1; 4. Bmp-1; 5. Fibrosis; 6. Mmp12; 7. Pcp; 8. Tll1; 9. Tll2

Tóm tắt

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 in vivo 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.