BI-2545的发现：一种能显著降低体内溶血磷脂酸水平的新型自分泌运动因子抑制剂。
Discovery of BI-2545: A Novel Autotaxin Inhibitor That Significantly Reduces LPA Levels in Vivo.
作者信息
Kuttruff Christian A, Ferrara Marco, Bretschneider Tom, Hoerer Stefan, Handschuh Sandra, Nosse Bernd, Romig Helmut, Nicklin Paul, Roth Gerald J
机构信息
Medicinal Chemistry, Drug Discovery Sciences, and Immunology & Respiratory, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany.
Boehringer Ingelheim Research Italia S.a.s. di BI IT S.r.l., Via G. Lorenzini 8, 20139 Milano, Italy.
出版信息
ACS Med Chem Lett. 2017 Nov 8;8(12):1252-1257. doi: 10.1021/acsmedchemlett.7b00312. eCollection 2017 Dec 14.
Abstract
In an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI-2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies.
摘要
为了寻找新的治疗方法来满足特发性肺纤维化患者未被满足的医疗需求，我们启动了一个项目来鉴定新的自分泌运动因子（ATX）抑制剂。从最近发表的一种化合物（PF-8380）开始，我们鉴定出了几种具有改善的药代动力学和安全性的高效ATX抑制剂。进一步的优化工作导致鉴定出一种个位数纳摩尔级的先导化合物（BI-2545），该化合物在体内能显著降低溶血磷脂酸（LPA）水平，因此被认为是进一步研究的有价值工具。
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