Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France.
Bioorg Med Chem Lett. 2013 Apr 15;23(8):2414-21. doi: 10.1016/j.bmcl.2013.02.018. Epub 2013 Feb 22.
Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.
从具有 Cyp3A4 风险的体外活性的 11β-HSD1 抑制剂开始，我们获得了一系列新的金刚烷脲，对人和啮齿动物的 11β-HSD1 酶均具有强大的抑制作用，并且与 Cyp3A4 无相互作用，经过合理设计可在靶组织中提供持久的抑制作用。最终优化得到了 SAR184841，它具有良好的口服药代动力学特性，在 2 型糖尿病的生理病理模型中表现出体内活性和代谢参数的改善。
