Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa-Tissue Factor Complex

Zhang Xiaojun; Glunz Peter W.; Johnson James A.; Jiang Wen; Jacutin-Porte Swanee; Ladziata Vladimir; Zou Yan; Phillips Monique S.; Wurtz Nicholas R.; Parkhurst Brandon; Rendina Alan R.; Harper Timothy M.; Cheney Daniel L.; Luettgen Joseph M.; Wong Pancras C.; Seiffert Dietmar; Wexler Ruth R.; Priestley E. Scott

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Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa-Tissue Factor Complex

机译：血液凝集因子VIIa-组织因子复合物的高度有效，选择性和口服生物利用性大环抑制剂的发现。

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Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated robust antithrombotic activity in a rabbit model of arterial thrombosis.

机译：组织因子（TF）/ VIIa因子复合物（TF-FVIIa）的抑制剂是有前途的新型抗凝剂，在临床前模型中显示出优异的疗效和最小的出血。从基于氨基异喹啉P1的大环抑制剂开始，对P'基团的优化导致产生了一系列通透性较差的高效和选择性TF-FVIIa抑制剂。氨基异喹啉的氟化降低了P1基团的碱性，并显着提高了渗透性。所得的先导化合物在口服给药的狗中是高度有效的，选择性的，并且在狗中获得了良好的药代动力学。此外，它在兔动脉血栓形成模型中显示出强大的抗血栓形成活性。

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《Journal of Medicinal Chemistry》 |2016年第15期|共13页
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Zhang Xiaojun; Glunz Peter W.; Johnson James A.; Jiang Wen; Jacutin-Porte Swanee; Ladziata Vladimir; Zou Yan; Phillips Monique S.; Wurtz Nicholas R.; Parkhurst Brandon; Rendina Alan R.; Harper Timothy M.; Cheney Daniel L.; Luettgen Joseph M.; Wong Pancras C.; Seiffert Dietmar; Wexler Ruth R.; Priestley E. Scott;
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1. Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa-Tissue Factor Complex [J] . Zhang Xiaojun, Glunz Peter W., Johnson James A., Journal of Medicinal Chemistry . 2016,第15期

机译：血液凝集因子VIIa-组织因子复合物的高度有效，选择性和口服生物利用性大环抑制剂的发现。
2. Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties. [J] . Pinto DJ, Galemmo RA Jr, Quan ML, Bioorganic and Medicinal Chemistry Letters . 2006,第21期

机译：发现具有中性P1部分的凝血因子Xa的有效，有效和口服生物利用抑制剂。
3. Discovery of 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-(2-fluoro-4- ((2'-dimethylaminomethyl)imidazol-1-yl)phenyl)-1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor. [J] . Quan ML, Lam PY, Han Q, Journal of Medicinal Chemistry . 2005,第6期

机译：1-（3'-氨基苯并恶唑-5'-基）-3-三氟甲基-N-（2-氟-4-（（2'-二甲基氨基甲基）咪唑-1-基）苯基）-1H-吡唑-5的发现-羧酰胺盐酸盐（razaxaban），一种高效，选择性和口服生物利用因子Xa抑制剂。
4. Factors that influence oral bioavailability; A cathepsin K inhibitor for human studies [C] . Daniel F. Veber American Peptide Symposium . 2009

机译：影响口腔生物利用度的因素;用于人类研究的组织蛋白酶K抑制剂
5. Inhibitor discovery against blood coagulation factor Xa and Bacillus anthracis protective antigen. [D] . Lee, Oukseub. 2009

机译：针对凝血因子Xa和炭疽芽孢杆菌保护性抗原的抑制剂发现。
6. Discovery of a Series of 3-Cinnoline Carboxamidesas Orally Bioavailable Highly Potent and Selective ATM Inhibitors [O] . Bernard Barlaam, *, Elaine Cadogan, 2018

机译：发现一系列3-Cinnoline羧酰胺作为口服生物利用度高活性和选择性ATM抑制剂
7. Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor [O] . Douglas S. Johnson, Cory Stiff, Scott E. Lazerwith, 2010

机译：发现PF-04457845：一种高效，口服生物的生物可利用和选择性尿素FAAH抑制剂

Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa-Tissue Factor Complex

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