当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-04 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00328 Kap-Sun Yeung 1 , Brett R Beno 1 , Kyle Parcella 1 , John A Bender 1 , Katherine A Grant-Young 1 , Andrew Nickel 1 , Prashantha Gunaga 2 , Prakash Anjanappa 2 , Rajesh Onkardas Bora 2 , Kumaravel Selvakumar 2 , Karen Rigat 1 , Ying-Kai Wang 1 , Mengping Liu 1 , Julie Lemm 1 , Kathy Mosure 1 , Steven Sheriff 3 , Changhong Wan 3 , Mark Witmer 3 , Kevin Kish 3 , Umesh Hanumegowda 1 , Xiaoliang Zhuo 1 , Yue-Zhong Shu 3 , Dawn Parker 1 , Roy Haskell 1 , Alicia Ng 3 , Qi Gao 4 , Elizabeth Colston 3 , Joseph Raybon 3 , Dennis M Grasela 3 , Kenneth Santone 1 , Min Gao 1 , Nicholas A Meanwell 1 , Michael Sinz 1 , Matthew G Soars 1 , Jay O Knipe 1 , Susan B Roberts 1 , John F Kadow 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-04 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00328 Kap-Sun Yeung 1 , Brett R Beno 1 , Kyle Parcella 1 , John A Bender 1 , Katherine A Grant-Young 1 , Andrew Nickel 1 , Prashantha Gunaga 2 , Prakash Anjanappa 2 , Rajesh Onkardas Bora 2 , Kumaravel Selvakumar 2 , Karen Rigat 1 , Ying-Kai Wang 1 , Mengping Liu 1 , Julie Lemm 1 , Kathy Mosure 1 , Steven Sheriff 3 , Changhong Wan 3 , Mark Witmer 3 , Kevin Kish 3 , Umesh Hanumegowda 1 , Xiaoliang Zhuo 1 , Yue-Zhong Shu 3 , Dawn Parker 1 , Roy Haskell 1 , Alicia Ng 3 , Qi Gao 4 , Elizabeth Colston 3 , Joseph Raybon 3 , Dennis M Grasela 3 , Kenneth Santone 1 , Min Gao 1 , Nicholas A Meanwell 1 , Michael Sinz 1 , Matthew G Soars 1 , Jay O Knipe 1 , Susan B Roberts 1 , John F Kadow 1
Affiliation
|
The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.
中文翻译：
发现丙型肝炎病毒 NS5B 复制酶 Palm Site Allosteric Inhibitor (BMS-929075) 进入 1 期临床研究
丙型肝炎病毒 (HCV) NS5B 复制酶是开发用于治疗慢性 HCV 感染的直接作用抗病毒药物的主要目标。受三种结构不同的 NS5B 棕榈位变构抑制剂的结合结构叠加的启发，高通量筛选命中邻氨基苯甲酸4、已知的苯并呋喃类似物5和苯并噻二嗪衍生物6，这是一种利用简单苯并呋喃模板7的优化过程作为碎片增长方法的起点。通过严格的亲脂性变化实现分子特性的微妙平衡对于实现高亲和力结合和严格的靶向吸收、分布、代谢和排泄曲线至关重要。这些努力导致了 BMS-929075 ( 37 )的发现，与早期先导相比，它保持了配体效率，在 HCV 复制子细胞的三联方案中表现出疗效，并且在临床前动物物种中表现出始终如一的高口服生物利用度和药代动力学参数。来自37项I 期临床研究的人体 PK 特性好于预期，表明 QD 给药的潜力很大。
更新日期：2017-05-04
中文翻译：
发现丙型肝炎病毒 NS5B 复制酶 Palm Site Allosteric Inhibitor (BMS-929075) 进入 1 期临床研究
丙型肝炎病毒 (HCV) NS5B 复制酶是开发用于治疗慢性 HCV 感染的直接作用抗病毒药物的主要目标。受三种结构不同的 NS5B 棕榈位变构抑制剂的结合结构叠加的启发，高通量筛选命中邻氨基苯甲酸4、已知的苯并呋喃类似物5和苯并噻二嗪衍生物6，这是一种利用简单苯并呋喃模板7的优化过程作为碎片增长方法的起点。通过严格的亲脂性变化实现分子特性的微妙平衡对于实现高亲和力结合和严格的靶向吸收、分布、代谢和排泄曲线至关重要。这些努力导致了 BMS-929075 ( 37 )的发现，与早期先导相比，它保持了配体效率，在 HCV 复制子细胞的三联方案中表现出疗效，并且在临床前动物物种中表现出始终如一的高口服生物利用度和药代动力学参数。来自37项I 期临床研究的人体 PK 特性好于预期，表明 QD 给药的潜力很大。
京公网安备 11010802027423号