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Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-08-24 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00070 Robert H Bradbury 1 , Rowena Callis 1 , Gregory R Carr 1 , Huawei Chen 2 , Edwin Clark 2 , Lyman Feron 1 , Steve Glossop 1 , Mark A Graham 1 , Maureen Hattersley 2 , Chris Jones 1 , Scott G Lamont 1 , Gilles Ouvry 3 , Anil Patel 1 , Joe Patel 2 , Alfred A Rabow 1 , Craig A Roberts 1 , Stephen Stokes 1 , Natalie Stratton 1 , Graeme E Walker 1 , Lara Ward 1 , David Whalley 1 , David Whittaker 1 , Gail Wrigley 1 , Michael J Waring 1, 4
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-08-24 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00070 Robert H Bradbury 1 , Rowena Callis 1 , Gregory R Carr 1 , Huawei Chen 2 , Edwin Clark 2 , Lyman Feron 1 , Steve Glossop 1 , Mark A Graham 1 , Maureen Hattersley 2 , Chris Jones 1 , Scott G Lamont 1 , Gilles Ouvry 3 , Anil Patel 1 , Joe Patel 2 , Alfred A Rabow 1 , Craig A Roberts 1 , Stephen Stokes 1 , Natalie Stratton 1 , Graeme E Walker 1 , Lara Ward 1 , David Whalley 1 , David Whittaker 1 , Gail Wrigley 1 , Michael J Waring 1, 4
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Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.
中文翻译：
一系列基于二价三唑并哒嗪的溴结构域和末端抑制剂的优化：(3R)-4-[2-[4-[1-(3-甲氧基-[1,2,4]三唑并[4,3-b]的发现]哒嗪-6-基)-4-哌啶基]苯氧基]乙基]-1,3-二甲基-哌嗪-2-酮 (AZD5153)
在这里，我们报告了一系列二价溴结构域和末端抑制剂的发现和优化。从观察先前程序中化合物的 BRD4 活性开始，针对 BRD4 效力和物理特性对化合物进行了优化。来自该活动的优化化合物表现出出色的药代动力学特征，并在异种移植研究中表现出高效的体外和体内 c-Myc 下调和肿瘤生长抑制作用。该化合物被选为开发候选物 AZD5153。由于二价结合和 BRD4 活性与细胞效力之间的明确相关性，该系列显示出增强的效力。
更新日期：2016-08-24
中文翻译：
一系列基于二价三唑并哒嗪的溴结构域和末端抑制剂的优化：(3R)-4-[2-[4-[1-(3-甲氧基-[1,2,4]三唑并[4,3-b]的发现]哒嗪-6-基)-4-哌啶基]苯氧基]乙基]-1,3-二甲基-哌嗪-2-酮 (AZD5153)
在这里，我们报告了一系列二价溴结构域和末端抑制剂的发现和优化。从观察先前程序中化合物的 BRD4 活性开始，针对 BRD4 效力和物理特性对化合物进行了优化。来自该活动的优化化合物表现出出色的药代动力学特征，并在异种移植研究中表现出高效的体外和体内 c-Myc 下调和肿瘤生长抑制作用。该化合物被选为开发候选物 AZD5153。由于二价结合和 BRD4 活性与细胞效力之间的明确相关性，该系列显示出增强的效力。
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