Discovery of TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10),ACS Medicinal Chemistry Letters

当前位置： X-MOL 学术 › ACS Med. Chem. Lett. › 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 TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10)
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2021-07-14 , DOI: 10.1021/acsmedchemlett.1c00273
Makoto Fushimi ₁ , Hannes Buck ₂ , Melanie Balbach ₂ , Anna Gorovyy ₂ , Jacob Ferreira ₂ , Thomas Rossetti ₂ , Navpreet Kaur ₂ , Lonny R Levin ₂ , Jochen Buck ₂ , Jonathan Quast ₃ , Joop van den Heuvel ₄ , Clemens Steegborn ₃ , Efrat Finkin-Groner ₁ , Stacia Kargman ₁ , Mayako Michino ₁ , Michael A Foley ₁ , Michael Miller ₁ , Nigel J Liverton ₁ , David J Huggins _{1,

5} , Peter T Meinke _{1,

2}

Affiliation

Soluble adenylyl cyclase (sAC) has gained attention as a potential therapeutic target given the role of this enzyme in intracellular signaling. We describe successful efforts to design improved sAC inhibitors amenable for in vivo interrogation of sAC inhibition to assess its potential therapeutic applications. This work culminated in the identification of TDI-10229 (12), which displays nanomolar inhibition of sAC in both biochemical and cellular assays and exhibits mouse pharmacokinetic properties sufficient to warrant its use as an in vivo tool compound.

中文翻译：

发现 TDI-10229：一种有效的口服生物可溶性腺苷酸环化酶 (sAC、ADCY10) 抑制剂

鉴于可溶性腺苷酸环化酶 (sAC) 在细胞内信号传导中的作用，它作为潜在的治疗靶点而受到关注。我们描述了设计改进的 sAC 抑制剂的成功努力，这些抑制剂适合体内sAC 抑制的研究，以评估其潜在的治疗应用。这项工作最终鉴定出 TDI-10229 ( 12 )，它在生化和细胞测定中显示出对 sAC 的纳摩尔抑制作用，并表现出足以保证其用作体内工具化合物的小鼠药代动力学特性。

更新日期：2021-08-12

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南