Glass D, Buschauer A, Tenor H, Bartel S, Will-Shahab L, Krause E G
Institut für Pharmazie, Universität Regensburg, Germany.
Arch Pharm (Weinheim). 1995 Oct;328(10):709-19. doi: 10.1002/ardp.19953281005.
A series of new positive inotropic agents was synthesized with the aim of combining the pharmacophores of the imidazolone-type phosphodiesterase (PDE) inhibitor enoximone and guanidine-type histamine H2 receptor agonists such as arpromidine. All compounds are para-substituted 4-benzoyl-5-alkyl-2-imidazolones. H2 agonism was incorporated by p-(hetero)arylalkyl substituents, in particular by an imidazolylpropyl guanidine group. In addition analogous ureas, cyanoguanidines, alkyl guanidine carboxylates, and amides were prepared. These functional groups were either directly attached to the phenyl ring or linked by an appropriate spacer. The compounds were screened for positive inotropic activity in the isolated electrically stimulated guinea pig papillary muscle and for inhibition of PDE III (cGMP-inhibited cAMP PDE, isolated from guinea pig heart). The cardiotonics obtained proved to be either PDE III inhibitors, some of them surmounting up to 3-fold the potency of enoximone, or pharmacological hybrids combining both PDE III inhibitor and histamine H2 receptor agonist activities. These hybrids were the most potent positive inotropic substances at the papillary muscle, probably due to their synergistic mechanism of action. The participation of histamine H2 receptors could be demonstrated in the papillary muscle preparation by pretreatment with the H2 antagonist famotidine (10 microM) as well as by further pharmacological experiments using isolated perfused hearts of guinea pigs and rats, isolated guinea pig right atria, adenylyl cyclase and H2 receptor binding assays. At equieffective concentrations the moderate PDE III inhibitor and histamine H2 agonist N1-(4-[(1,3-dihydro-5-methyl-2-oxo-3H-imidazol-4-yl)-carbonyl]phenyl)-N2 - [3-(1H-imidazol-4-yl)propyl]guanidine 65 and the 5-ethyl homologue 66 were about 2 and 10 times more potent than enoximone at the papillary muscle. Moreover, both compounds produced a 2.5-fold higher maximal response than the reference compound.
为了将咪唑啉酮型磷酸二酯酶（PDE）抑制剂依诺昔酮和胍型组胺H2受体激动剂（如阿普米定）的药效基团结合起来，合成了一系列新型正性肌力药物。所有化合物均为对位取代的4-苯甲酰基-5-烷基-2-咪唑啉酮。通过对（杂）芳基烷基取代基，特别是咪唑基丙基胍基团引入H2激动作用。此外，还制备了类似的脲、氰基胍、烷基胍羧酸盐和酰胺。这些官能团要么直接连接到苯环上，要么通过合适的间隔基相连。在分离的电刺激豚鼠乳头肌中筛选化合物的正性肌力活性，并在豚鼠心脏中筛选对PDE III（cGMP抑制的cAMP PDE）的抑制作用。所得到的强心剂被证明要么是PDE III抑制剂，其中一些的效力比依诺昔酮高3倍，要么是兼具PDE III抑制剂和组胺H2受体激动剂活性的药理杂合体。这些杂合体是乳头肌中最有效的正性肌力物质，这可能是由于它们的协同作用机制。组胺H2受体的参与可以通过用H2拮抗剂法莫替丁（10μM）预处理在乳头肌制备中得到证明，也可以通过使用豚鼠和大鼠的离体灌流心脏、离体豚鼠右心房、腺苷酸环化酶和H2受体结合试验的进一步药理实验得到证明。在等效应浓度下，中度PDE III抑制剂和组胺H2激动剂N1-（4-[(1,3-二氢-5-甲基-2-氧代-3H-咪唑-4-基）羰基]苯基）-N2-[3-（1H-咪唑-4-基）丙基]胍65和5-乙基同系物66在乳头肌上的效力比依诺昔酮分别高约2倍和10倍。此外，这两种化合物产生的最大反应比参比化合物高2.5倍。
