Earl R A, Zaczek R, Teleha C A, Fisher B N, Maciag C M, Marynowski M E, Logue A R, Tam S W, Tinker W J, Huang S M, Chorvat R J
The DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
J Med Chem. 1998 Nov 5;41(23):4615-22. doi: 10.1021/jm9803424.
In an effort to improve the pharmacokinetic and pharmacodynamic properties of the cognition-enhancer linopirdine (DuP 996), a number of core structure analogues were prepared in which the 4-pyridyl pendant group was systematically replaced with 2-fluoro-4-pyridyl. This strategy resulted in the discovery of several compounds with improved activity in acetylcholine (ACh) release-enhancing assays, in vitro and in vivo. The most effective compound resulting from these studies, 10, 10-bis[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (9), is between 10 and 20 times more potent than linopirdine in increasing extracellular hippocampal ACh levels in the rat with a minimum effective dose of 1 mg/kg. In addition to superior potency, 9 possesses an improved pharmacokinetic profile compared to that of linopirdine. The half-life of 9 (2 h) in rats is 4-fold greater than that of linopirdine (0.5 h), and it showed a 6-fold improvement in brain-plasma distribution over linopirdine. On the basis of its pharmacologic, pharmacokinetic, absorption, and distribution properties, 9 (DMP543) has been advanced for clinical evaluation as a potential palliative therapeutic for treatment of Alzheimer's disease.
为了改善认知增强剂利诺吡啶（DuP 996）的药代动力学和药效学性质，制备了一系列核心结构类似物，其中4-吡啶侧基被2-氟-4-吡啶系统取代。该策略导致发现了几种在体外和体内乙酰胆碱（ACh）释放增强试验中活性有所提高的化合物。这些研究中最有效的化合物10,10-双[（2-氟-4-吡啶基）甲基]-9（10H）-蒽酮（9），在大鼠海马细胞外ACh水平增加方面比利诺吡啶强10至20倍，最小有效剂量为1mg/kg。除了效力更强外，9与利诺吡啶相比还具有改善的药代动力学特征。9在大鼠体内的半衰期（2小时）比利诺吡啶（0.5小时）长4倍，并且其脑-血浆分布比利诺吡啶提高了6倍。基于其药理、药代动力学、吸收和分布特性，9（DMP543）已被推进用于临床评估，作为治疗阿尔茨海默病的潜在姑息治疗药物。
