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Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-05-26 , DOI: 10.1021/acs.jmedchem.0c00464
Wu Yang 1 , Yufeng Wang 1 , Amy Lai 1 , Charles G Clark 1 , James R Corte 1 , Tianan Fang 1 , Paul J Gilligan 1 , Yoon Jeon 1 , Kumar B Pabbisetty 1 , Richard A Rampulla 1 , Arvind Mathur 1 , Mahammed Kaspady 2 , Premsai Rai Neithnadka 2 , Arunachalam Arumugam 2 , Sivashankaran Raju 2 , Karen A Rossi 1 , Joseph E Myers 1 , Steven Sheriff 1 , Zhen Lou 1 , Joanna J Zheng 1 , Silvi A Chacko 1 , Jeffrey M Bozarth 1 , Yiming Wu 1 , Earl J Crain 1 , Pancras C Wong 1 , Dietmar A Seiffert 1 , Joseph M Luettgen 1 , Patrick Y S Lam 1 , Ruth R Wexler 1 , William R Ewing 1
Affiliation  

Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure–activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f, a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.

中文翻译:

在临床前物种中发现具有抗血栓形成活性的高亲和力,口服可生物利用的大环FXIa抑制剂。

口服因子XIa(FXIa)抑制剂可能会提供一种有前途的新抗栓治疗方法,与现有的抗栓剂相比,它对出血风险的改善作用更大。在本文中,我们报道了先前公开的环状氨基甲酸酯P1接头的应用,其在基于咪唑的13元大环化合物至12元大环化合物中提供了改善的口服生物利用度。这导致鉴定出具有所需FXIa抑制能力和良好的口服生物利用度但体内清除率较高的化合物4。进一步的结构-活性关系(SAR)研究,以取代咪唑核心的杂环核心修饰以及P1基团的各种连接基导致发现化合物6f,一种有效的FXIa抑制剂,对大多数相关丝氨酸蛋白酶具有选择性。化合物6f在多个临床前物种中也表现出出色的药代动力学(PK)谱(高口服生物利用度和低清除率)。在保持止血的剂量下,化合物6f在兔功效模型中获得了强大的抗血栓形成功效。
更新日期:2020-07-09
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