公开(公告)号：US20150184142A1

公开(公告)日：2015-07-02

申请号：US14406163

申请日：2013-06-07

Applicant: Biogen Idec MA Inc.

Inventor： Vu Phong Hong ,  Adam R. Mezo ,  Joe Salas ,  Robert Peters

IPC: C12N9/64 ,  A61K38/48

CPC classification number: C12N9/6437 ,  A61K38/02 ,  A61K38/36 ,  A61K38/4846 ,  C12N9/6432

Abstract: The present disclosure provides protease-activatable procoagulant compounds comprising a procoagulant polypeptide, e.g., a procoagulant peptide and/or clotting factor, and a linker comprising a protease-cleavable substrate (e.g., a synthetic thrombin substrate) and a self-immolative spacer (e.g., p-amino benzyl carbamate). Upon cleavage of the protease-cleavable substrate by a protease (e.g., thrombin), the self-immolative spacer cleaves itself from the procoagulant polypeptide such that the polypeptide is in an underivatized and active form. Also provided are pharmaceutical compositions, methods for treating bleeding disorders using the disclosed compounds, methods of enhancing in vivo efficacy of procoagulant polypeptides, methods of increasing the efficacy of proteolytic cleavage of compounds comprising procoagulant polypeptides, methods of activating procoagulant polypeptides, and methods of releasing a procoagulant polypeptide from a heterologous moiety such as PEG.

Abstract translation: 本公开提供了包含促凝血多肽，例如促凝血肽和/或凝血因子的蛋白酶活化的促凝血化合物，以及包含蛋白酶切割底物（例如，合成凝血酶底物）和自发性隔离物（例如， ，对氨基苄基氨基甲酸酯）。 在通过蛋白酶（例如凝血酶）裂解蛋白酶可切割底物之后，自消除性间隔区从促凝血多肽切割自身，使得多肽处于未衍生的和活性的形式。 还提供了药物组合物，使用所公开的化合物治疗出血性疾病的方法，增强促凝血多肽的体内功效的方法，增加包含促凝血多肽的化合物的蛋白水解切割的功效的方法，活化促凝血多肽的方法和释放方法 来自异源部分如PEG的促凝血多肽。