Department of Chemistry, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
J Med Chem. 2012 Jul 12;55(13):6162-75. doi: 10.1021/jm300611v. Epub 2012 Jun 22.
A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.
一系列二苯并吡啶乙胺（DPPE）衍生物被鉴定出具有有效的 CETP 抑制作用。在最初的先导化合物 7 中取代不稳定的酯官能团，生成了一系列酰胺和脲。为了提高 DPPE 系列的效力，进一步对其进行优化，发现了环戊基脲 15d，它在 hCETP/apoB-100 双转基因小鼠中降低了胆固醇酯转移活性（达到预给药水平的 48%）。15d 的 PK 特征并不理想，进一步优化 N-末端得到酰胺 20，其 PK 特征得到改善，在转基因 hCETP/apoB-100 小鼠和仓鼠中具有强大的疗效。尽管持续高暴露，但化合物 20 在遥测大鼠中没有导致平均动脉血压或心率出现显著变化。
