Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer was written by Han, Xin;Zhao, Lijie;Xiang, Weiguo;Qin, Chong;Miao, Bukeyan;McEachern, Donna;Wang, Yu;Metwally, Hoda;Wang, Lu;Matvekas, Aleksas;Wen, Bo;Sun, Duxin;Wang, Shaomeng. And the article was included in Journal of Medicinal Chemistry in 2021.Synthetic Route of C16H22N2O4 This article mentions the following:
Proteolysis targeting chimera (PROTAC) small-mol. degraders have emerged as a promising new type of therapeutic agents, but the design of PROTAC degraders with excellent oral pharmacokinetics is a major challenge. In this study, we present our strategies toward the discovery of highly potent PROTAC degraders of androgen receptor (AR) with excellent oral pharmacokinetics. Employing thalidomide to recruit cereblon/cullin 4A E3 ligase and through the rigidification of the linker, we discovered highly potent AR degraders with good oral pharmacokinetic properties in mice with ARD-2128 (I) being the best compound ARD-2128 achieves 67% oral bioavailability in mice, effectively reduces AR protein and suppresses AR-regulated genes in tumor tissues with oral administration, leading to the effective inhibition of tumor growth in mice without signs of toxicity. This study supports the development of an orally active PROTAC AR degrader for the treatment of prostate cancer and provides insights and guidance into the design of orally active PROTAC degraders. In the experiment, the researchers used many compounds, for example, 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)benzoic acid (cas: 162046-66-4Synthetic Route of C16H22N2O4).
4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)benzoic acid (cas: 162046-66-4) belongs to piperazine derivatives. A form in which piperazine is commonly available industrially is as the hexahydrate, C4H10N2. 6H2O, which melts at 44 °C and boils at 125â?30 °C. Intermediate for a wide range of pharmaceuticals, polymers, dyes, corrosion inhibitors, rubber accelerators and surfactants.Synthetic Route of C16H22N2O4
Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics