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Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-02 , DOI: 10.1021/acs.jmedchem.9b01768 James R Corte 1 , Donald J P Pinto 1 , Tianan Fang 1 , Honey Osuna 1 , Wu Yang 1 , Yufeng Wang 1 , Amy Lai 1 , Charles G Clark 1 , Jung-Hui Sun 2 , Richard Rampulla 2 , Arvind Mathur 2 , Mahammed Kaspady 3 , Premsai Rai Neithnadka 3 , Yi-Xin Cindy Li 1 , Karen A Rossi 1 , Joseph E Myers 2 , Steven Sheriff 2 , Zhen Lou 4 , Timothy W Harper 4 , Christine Huang 4 , Joanna J Zheng 4 , Jeffrey M Bozarth 4 , Yiming Wu 4 , Pancras C Wong 4 , Earl J Crain 4 , Dietmar A Seiffert 4 , Joseph M Luettgen 4 , Patrick Y S Lam 1 , Ruth R Wexler 1 , William R Ewing 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-02 , DOI: 10.1021/acs.jmedchem.9b01768 James R Corte 1 , Donald J P Pinto 1 , Tianan Fang 1 , Honey Osuna 1 , Wu Yang 1 , Yufeng Wang 1 , Amy Lai 1 , Charles G Clark 1 , Jung-Hui Sun 2 , Richard Rampulla 2 , Arvind Mathur 2 , Mahammed Kaspady 3 , Premsai Rai Neithnadka 3 , Yi-Xin Cindy Li 1 , Karen A Rossi 1 , Joseph E Myers 2 , Steven Sheriff 2 , Zhen Lou 4 , Timothy W Harper 4 , Christine Huang 4 , Joanna J Zheng 4 , Jeffrey M Bozarth 4 , Yiming Wu 4 , Pancras C Wong 4 , Earl J Crain 4 , Dietmar A Seiffert 4 , Joseph M Luettgen 4 , Patrick Y S Lam 1 , Ruth R Wexler 1 , William R Ewing 1
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Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge. A two-pronged strategy, which focused on replacement of the imidazole scaffold and the design of new P1 groups, led to the discovery of potent, orally bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover, pyridine-based macrocycle 19, possessing the phenylimidazole carboxamide P1, exhibited excellent selectivity against relevant blood coagulation enzymes and displayed antithrombotic efficacy in a rabbit thrombosis model.
中文翻译：
XIa的强效，口服生物利用度和有效大环抑制剂。发现基于苯基的大环具有苯基苯甲酰胺P1基团。
XIa因子（FXIa）抑制剂是有前途的新型抗凝剂，在临床前血栓形成模型中显示出优异的疗效，对止血的影响极小。有效和选择性的FXIa抑制剂的口服生物利用性的发现一直是一个挑战。在这里，我们描述了基于咪唑的大环系列的优化以及我们在应对这一挑战方面的初步进展。着眼于取代咪唑支架和设计新的P1基团的两管齐下的策略导致发现了有效的，口服可生物利用的基于吡啶的大环FXIa抑制剂。此外，具有苯基咪唑羧酰胺P1的基于吡啶的大环化合物19在兔血栓形成模型中对相关的凝血酶表现出优异的选择性，并显示出抗血栓形成的功效。
更新日期：2020-01-04
中文翻译：
XIa的强效，口服生物利用度和有效大环抑制剂。发现基于苯基的大环具有苯基苯甲酰胺P1基团。
XIa因子（FXIa）抑制剂是有前途的新型抗凝剂，在临床前血栓形成模型中显示出优异的疗效，对止血的影响极小。有效和选择性的FXIa抑制剂的口服生物利用性的发现一直是一个挑战。在这里，我们描述了基于咪唑的大环系列的优化以及我们在应对这一挑战方面的初步进展。着眼于取代咪唑支架和设计新的P1基团的两管齐下的策略导致发现了有效的，口服可生物利用的基于吡啶的大环FXIa抑制剂。此外，具有苯基咪唑羧酰胺P1的基于吡啶的大环化合物19在兔血栓形成模型中对相关的凝血酶表现出优异的选择性，并显示出抗血栓形成的功效。
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