Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA.
Inception Sciences, Suite 100, 5871 Oberlin Drive, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2019 Feb 1;29(3):503-508. doi: 10.1016/j.bmcl.2018.12.045. Epub 2018 Dec 21.
We previously published on the design and synthesis of novel, potent and selective PPARα antagonists suitable for either i.p. or oral in vivo administration for the potential treatment of cancer. Described herein is SAR for a subsequent program, where we set out to identify selective and potent PPARα/δ dual antagonist molecules. Emerging literature indicates that both PPARα and PPARδ antagonism may be helpful in curbing the proliferation of certain types of cancer. This dual antagonism could also be used to study PPARs in other settings. After testing for selective and dual potency, off-target counter screening, metabolic stability, oral bioavailability and associated toxicity, compound 11, the first reported PPARα/δ dual antagonist was chosen for more advanced preclinical evaluation.
我们之前发表过关于新型、有效且选择性的 PPARα 拮抗剂的设计和合成的文章，这些拮抗剂适合通过腹腔内或口服途径进行体内给药，可用于癌症的潜在治疗。本文描述了后续计划的 SAR，我们旨在确定选择性和有效的 PPARα/δ 双重拮抗剂分子。新兴文献表明，PPARα 和 PPARδ 的拮抗作用都可能有助于抑制某些类型癌症的增殖。这种双重拮抗作用也可用于研究其他环境中的 PPAR。在对选择性和双重效力、非靶点反向筛选、代谢稳定性、口服生物利用度和相关毒性进行测试后，选择了第一个报道的 PPARα/δ 双重拮抗剂 11 进行更先进的临床前评估。
