Taylor Alexander M, Vaswani Rishi G, Gehling Victor S, Hewitt Michael C, Leblanc Yves, Audia James E, Bellon Steve, Cummings Richard T, Côté Alexandre, Harmange Jean-Christophe, Jayaram Hari, Joshi Shivangi, Lora Jose M, Mertz Jennifer A, Neiss Adrianne, Pardo Eneida, Nasveschuk Christopher G, Poy Florence, Sandy Peter, Setser Jeremy W, Sims Robert J, Tang Yong, Albrecht Brian K
Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
ACS Med Chem Lett. 2015 Mar 25;7(2):145-50. doi: 10.1021/ml500411h. eCollection 2016 Feb 11.
Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.
已证明抑制BET家族（BRD4是其中一员）的溴结构域，可在体内降低myc和白细胞介素（IL）6，这两种标志物分别与癌症和炎症性疾病的治疗相关。在此，我们报告了取代苯并[b]异恶唑并[4,5-d]氮杂卓和苯并三唑并[4,3-d][1,4]二氮杂卓作为BRD4溴结构域的片段衍生新型抑制剂。这些系列的化合物在细胞中具有强效和选择性，随后对微粒体稳定性的优化产生了在小鼠中表现出剂量和时间依赖性降低血浆IL-6的代表化合物。
