Wu Yong-Jin, Guernon Jason, Shi Jianliang, Ditta Jonathan, Robbins Kevin J, Rajamani Ramkumar, Easton Amy, Newton Amy, Bourin Clotilde, Mosure Kathleen, Soars Matthew G, Knox Ronald J, Matchett Michele, Pieschl Rick L, Post-Munson Debra J, Wang Shuya, Herrington James, Graef John, Newberry Kimberly, Bristow Linda J, Meanwell Nicholas A, Olson Richard, Thompson Lorin A, Dzierba Carolyn
Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
J Med Chem. 2017 Mar 23;60(6):2513-2525. doi: 10.1021/acs.jmedchem.6b01918. Epub 2017 Mar 10.
By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Na1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.
通过利用哌啶4中的某些特性，我们开发了一系列新型的基于环己胺和哌啶的苯磺酰胺，作为强效且选择性的Na1.7抑制剂。然而，早期类似物之一的化合物24，即使在口服剂量为100 mpk时，也未能在小鼠福尔马林试验中减少2期退缩反应，这是由于膜通透性差导致背根神经节（DRG）暴露不足所致。两种膜通透性得到改善的类似物在口服剂量为30 mpk时显示DRG浓度大幅增加，但令人困惑的是，其中只有一种在福尔马林试验中有效。需要更多数据来理解疗效与暴露关系之间的脱节。
