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.

中文翻译：

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骨形态发生蛋白1的反向异羟肟酸酯抑制剂。

抑制骨形态发生蛋白1（BMP1）是一种治疗纤维化的潜在方法，因为需要BMP1（锌金属蛋白酶家族的成员）才能将前胶原转化为胶原蛋白。发现了一类新型的异羟肟酸酯BMP1抑制剂，并获得了与BMP1的共晶结构。观察到的结合模式是独特的，因为小分子占据了金属蛋白酶口袋的非主要部分，从而提供了建立金属蛋白酶选择性的机会。初始命中的结构指导修饰导致鉴定了口服体内对其他金属蛋白酶具有选择性的工具化合物。由于针对该化学类别的细胞色素P450 3A4具有不可逆的抑制作用，因此可以通过优化皮下注射系列来管理潜在药物相互作用的风险。