Small Molecules Innovation, Research & Development, Bayer Pharmaceuticals, Wuppertal, Germany.
Small Molecules Innovation, Research & Development, Bayer Pharmaceuticals, Wuppertal, Germany.
Eur J Med Chem. 2019 Feb 1;163:763-778. doi: 10.1016/j.ejmech.2018.11.045. Epub 2018 Nov 20.
The A adenosine receptor is a G protein-coupled receptor that belongs to the four member family of adenosine receptors: A, A, A, A. While adenosine-mediated A receptor signaling attenuates acute inflammation, facilitates tissue adaptation to hypoxia, and induces increased ischemia tolerance under conditions of an acute insult, persistently elevated adenosine levels and A receptor signaling are characteristics of a number of chronic disease states. In this report we describe the discovery of certain thienouracils (thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones) as antagonists of the A adenosine receptor by high-throughput screening from our corporate substance collection. The structure optimization of the initial screening hits led to BAY-545, an A receptor antagonist that was suitable for in vivo testing. The structure optimization work, SAR that was derived from there, as well as the properties of BAY-545 are also described. In vivo efficacy of BAY-545 was demonstrated in two models of lung fibrosis and data is presented.
A 腺苷受体是一种 G 蛋白偶联受体，属于腺苷受体的四个成员家族：A、A、A、A。虽然腺苷介导的 A 受体信号转导可减弱急性炎症，促进组织对缺氧的适应，并在急性损伤条件下诱导增加缺血耐受，但持续升高的腺苷水平和 A 受体信号转导是许多慢性疾病状态的特征。在本报告中，我们描述了通过高通量筛选从我们的公司物质库中发现某些噻吩并[2,3-d]嘧啶-2,4(1H,3H)-二酮（thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones）作为 A 腺苷受体拮抗剂的情况。对初始筛选命中物的结构优化导致了 BAY-545 的产生，BAY-545 是一种适合体内测试的 A 受体拮抗剂。还描述了结构优化工作、由此衍生的 SAR 以及 BAY-545 的特性。BAY-545 在两种肺纤维化模型中的体内功效得到了证明，并提供了相关数据。
