Che, Jinxin; Dai, Xiaoyang; Gao, Jian; Sheng, Haichao; Zhan, Wenhu; Lu, Yang; Li, Dan; Gao, Zizheng; Jin, Zegao; Chen, Binhui; Luo, Peihua; Yang, Bo; Hu, Yongzhou; He, Qiaojun; Weng, Qinjie; Dong, Xiaowu published their research in Journal of Medicinal Chemistry in 2021. The article was titled 《Discovery of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity》.Electric Literature of C9H15BN2O2 The article contains the following contents:
Here, the inhibition of Akt2 isoenzyme might be a driver for keratinocyte apoptosis was demonstrate, which promotes us to search for new selective Akt inhibitor compounds I [R1 = 4-F, 3,4-di-F, 3,5-di-F; R2 = 2-F, 3-F, 2-Cl, 2,6-di-F, 2,5-di-F, 2-F-6-Cl; R3 = H, Cl, Br; R4 = H, Me, Et] with an improved cutaneous safety property. According to our previous research, compound I [R1 = 3,4-di-F; R2 = R3 = H; R4 = Me] was selected for further optimization for overcoming the disadvantages of compound II, including high Akt2 inhibition and high toxicity against HaCaT keratinocytes. The dihedral angle-based design and mol. dynamics simulation led to the identification of Hu7691 I [R1 = 3,4-di-F; R2 = 2-F; R3 = H; R4 = Me] that achieves a 24-fold selectivity between Akt1 and Akt2. Hu7691 I [R1 = 3,4-di-F; R2 = 2-F; R3 = H; R4 = Me] exhibited low activity in inducing HaCaT apoptosis, promising kinase selectivity, and excellent anticancer cell proliferation potencies. Based on the superior results of safety property, pharmacokinetic profile, and in vivo efficacy, the National Medical Products Administration (NMPA) approved the investigational new drug (IND) application of Hu7691 I [R1 = 3,4-di-F; R2 = 2-F; R3 = H; R4 = Me]. In the part of experimental materials, we found many familiar compounds, such as 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(cas: 844501-71-9Electric Literature of C9H15BN2O2)
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(cas: 844501-71-9) belongs to pyrazoles. Pyrazoles are commonly used scaffold molecules in drug discovery projects. The use of pyrazole derivatives is based on their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, sedative, muscle relaxant, neuroleptic, anticonvulsant, monoamine oxidase inhibitory, antidiabetic and antibacterial activities. Electric Literature of C9H15BN2O2
Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics