Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Health Building 2, Houston, TX 77204, USA.
Calibr, a Division of The Scripps Research Institute, La Jolla, CA, 92037, USA.
Bioorg Med Chem Lett. 2023 Jun 15;90:129328. doi: 10.1016/j.bmcl.2023.129328. Epub 2023 May 15.
BMS906024, a γ-secretase inhibitor that blocks Notch signaling, was previously shown to inhibit Cryptosporidium parvum growth in vitro. A structure-activity relationship (SAR) analysis of BMS906024 reported herein demonstrates the importance of the stereochemistry of the C-3 benzodiazepine and the succinyl β-substituent. However, concomitant removal of the succinyl α-substituent and switching the primary amide with secondary amides was tolerated. For example, 32 (SH287) inhibited C. parvum growth in HCT-8 host cells with an EC = 6.4 nM and an EC = 16 nM; however, blocking C. parvum growth with BMS906024 derivatives was correlative with inhibition of Notch signaling, highlighting that additional SAR analysis will be needed to separate these two activities.
BMS906024 是一种 γ-分泌酶抑制剂，可阻断 Notch 信号通路，先前已被证明可抑制体外微小隐孢子虫的生长。本文对 BMS906024 的构效关系 (SAR) 分析表明，C-3 苯并二氮杂䓬和琥珀酰 β-取代基的立体化学非常重要。然而，同时去除琥珀酰 α-取代基并将伯酰胺转换为仲酰胺也是可以接受的。例如，化合物 32（SH287）以 EC=6.4 nM 和 EC=16 nM 的浓度抑制 HCT-8 宿主细胞中的微小隐孢子虫生长；然而，用 BMS906024 衍生物阻断微小隐孢子虫的生长与 Notch 信号通路的抑制相关，这表明需要进一步的 SAR 分析来分离这两种活性。
