ACS medicinal chemistry letters · 2018
Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1.
СтатьяНазвание и аннотация: Перевод в очереди
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Kallander Lara S, Washburn David, Hilfiker Mark A, Eidam Hilary Schenck, Lawhorn Brian G, Prendergast Joanne, Fox Ryan, Dowdell Sarah, Manns Sharada, Hoang Tram, Zhao Steve, Ye Guosen, Hammond Marlys, Holt Dennis A, Roethke Theresa, Hong Xuan, Reid Robert A, Gampe Robert, Zhang Hong, Diaz Elsie, Rendina Alan R, Quinn Amy M, Willette Bob
Аннотация
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.