Perchonock C D, Uzinskas I, Ku T W, McCarthy M E, Bondinell W E, Volpe B W, Gleason J G, Weichman B M, Muccitelli R M, DeVan J F
Prostaglandins. 1985 Jan;29(1):75-81. doi: 10.1016/0090-6980(85)90152-2.
A series of desamino-2-nor-leukotriene analogs has been prepared by the reaction of various thiols with several methyl trans-4,5-epoxy-6Z-alkenoates, followed by deprotection. The products were assessed for their ability to antagonize the LTD4-induced contraction of the isolated guinea pig trachea. Several compounds displayed potent leukotriene antagonist activity, i.e., KB values in the sub-micromolar range, while only minimally affecting basal airway tone. The most potent analog, 4-hydroxy-5-(2-carboxyethylthio)-6Z-nonadecenoic acid, antagonized both LTD4- and LTE4-induced contractions of the trachea in an apparently competitive fashion. These agents possess increased potency relative to SK&F 101132, the first leukotriene analog identified as having LT-antagonist activity. Thus, these results demonstrate that deletion of the peptide amino group can produce leukotriene analogs which have minimal intrinsic contractile activity on the isolated guinea pig trachea, yet possess potent leukotriene-antagonistic effects.
通过各种硫醇与几种反式-4,5-环氧-6Z-链烯酸甲酯反应，随后进行脱保护，制备了一系列脱氨基-2-去甲白三烯类似物。评估了这些产物拮抗LTD4诱导的离体豚鼠气管收缩的能力。几种化合物表现出强效的白三烯拮抗剂活性，即KB值在亚微摩尔范围内，而对基础气道张力的影响极小。最有效的类似物4-羟基-5-(2-羧乙基硫基)-6Z-十九碳烯酸，以明显竞争性的方式拮抗LTD4和LTE4诱导的气管收缩。相对于第一个被鉴定具有LT拮抗剂活性的白三烯类似物SK&F 101132，这些药物的效力有所提高。因此，这些结果表明，肽氨基的缺失可以产生对白三烯类似物，它们对离体豚鼠气管的内在收缩活性极小，但具有强效的白三烯拮抗作用。
