Based on our previous work, a series of N-phenyl-3-methoxy-4-pyridinone derivatives were designed as orally bioavailable dual functional agents for therapy of Alzheimer’s disease, through introducing alkyloxy moiety into 4-pyridinone ring to avoid the possible phase II metabolism of 3-hydroxy-4-pyridinone in lead compound 3-hydroxy-2-methyl-1-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-pyridin-4(1H)-one (4). In vitro studies indicated that most of these compounds exhibit excellent H₃ receptor antagonistic activities and potent self-induced Aβ_1-40/Aβ_1-42 aggregation inhibitory activities. In particular, 3-methoxy-1-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-pyridin-4(1H)-one (7i) demonstrated IC₅₀ value of 0.52 nM in H₃R antagonism and good selectivity over other histamine receptor subtypes. The transmission electron microscopy (TEM) images showed that compound 7i can inhibit self-mediated Aβ_1-40/Aβ_1-42 aggregation efficiently. As expected, it exhibited desirable pharmacokinetic properties in plasma and good BBB permeability. Furthermore, compound 7i can efficiently block (R)-α-methylhistamine- induced dipsogenia and reverse scopolamine-induced learning deficits of rats. All above results indicated that compound 7i was a promising orally bioavailable dual functional agents with potential use in the treatment of Alzheimer’s disease.

根据我们以前的工作，通过将烷氧基部分引入4-吡啶酮环中以避免可能的II期，设计了一系列N-苯基-3-甲氧基-4-吡啶酮衍生物作为口服生物可利用的双重功能药物，用于治疗阿尔茨海默氏病铅化合物的3-羟基-4-吡啶酮的代谢3-羟基-2-甲基-1-（4-（3-（吡咯烷-1-基）丙氧基）苯基） -吡啶-4-（1 ħ） -酮（ 4）。体外研究表明，这些化合物大多数都具有出色的H ₃受体拮抗活性和强力的自诱导_Aβ1-40 / _Aβ1-42聚集抑制活性。特别是，3-甲氧基-1-（4-（3-（吡咯烷基-1-基）丙氧基）苯基）-吡啶-4（1H）-一（7i）在H ₃ R拮抗作用中显示IC ₅₀值为0.52 nM。对其他组胺受体亚型具有良好的选择性。透射电子显微镜（TEM）图像显示化合物7i可有效抑制自我介导的_Aβ1-40 / _Aβ1-42聚集。如预期的那样，它在血浆中表现出理想的药代动力学性质和良好的BBB渗透性。此外，化合物7i可以有效地阻止（R）-α-甲基组胺诱导的成瘾症和反向东pol碱诱导的大鼠学习障碍。所有以上结果表明，化合物7i是有希望的口服生物可利用的双重功能剂，具有潜在的治疗阿尔茨海默氏病的用途。