Carter J P, Noronha-Blob L, Audia V H, Dupont A C, McPherson D W, Natalie K J, Rzeszotarski W J, Spagnuolo C J, Waid P P, Kaiser C
Nova Pharmaceutical Corporation, Baltimore, Maryland 21224-6522.
J Med Chem. 1991 Oct;34(10):3065-74. doi: 10.1021/jm00114a016.
Oxybutynin chloride [4-(diethylamino)-2-butynyl alpha-cyclohexyl-alpha-hydroxybenzeneacetate hydrochloride, Ditropan] is widely used for the relief of symptoms in neurogenic bladder. This is a result of its combined anticholinergic, antispasmodic, and local anesthetic activities. In a study directed toward development of agents possessing the beneficial properties of oxybutynin, but having a longer duration of action, a series of metabolically more stable keto analogues of the parent ester, i.e. substituted 7-amino-1-hydroxy-5-heptyn-2-ones along with some analogues and derivatives, was prepared and evaluated for in vitro and in vivo antimuscarinic action in guinea pig preparations. Several members of the series were potent antimuscarinics having a longer duration of activity than that of oxybutynin in a guinea pig cystometrogram model. On the basis of its in vitro and in vivo antimuscarinic activity, coupled with a 5-fold greater duration of action than that of oxybutynin, 1-cyclobutyl-7-(dimethylamino)-1-hydroxy-1-phenyl-5-heptyn-2-one (14b) was selected for clinical evaluation.
氯化奥昔布宁[4-(二乙氨基)-2-丁炔基α-环己基-α-羟基苯乙酸酯盐酸盐，得妥]被广泛用于缓解神经源性膀胱的症状。这是其抗胆碱能、解痉和局部麻醉活性共同作用的结果。在一项旨在开发具有奥昔布宁有益特性但作用持续时间更长的药物的研究中，制备了一系列母体酯的代谢更稳定的酮类似物，即取代的7-氨基-1-羟基-5-庚炔-2-酮以及一些类似物和衍生物，并在豚鼠制剂中对其体外和体内抗毒蕈碱作用进行了评估。在豚鼠膀胱测压图模型中，该系列中的几个成员是强效抗毒蕈碱剂，其活性持续时间比奥昔布宁更长。基于其体外和体内抗毒蕈碱活性，以及比奥昔布宁长5倍的作用持续时间，选择了1-环丁基-7-(二甲氨基)-1-羟基-1-苯基-5-庚炔-2-酮(14b)进行临床评估。
