作为血栓素A2拮抗剂的7-氧杂双环[2.2.1]庚基羧酸：氮杂ω-链类似物

7-Oxabicyclo[2.2.1]heptyl carboxylic acids as thromboxane A2 antagonists: aza omega-chain analogues.

作者信息

Nakane M, Reid J A, Han W C, Das J, Truc V C, Haslanger M F, Garber D, Harris D N, Hedberg A, Ogletree M L

机构信息

Department of Chemistry, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.

出版信息

J Med Chem. 1990 Sep;33(9):2465-76. doi: 10.1021/jm00171a021.

DOI:10.1021/jm00171a021

PMID:2391688

Abstract

A novel bicyclic prostaglandin analogue, [1S-[1 alpha, 2 alpha (Z), 3 alpha, 4 alpha]]-7-[3-[[[[(1- Oxoheptyl)amino]acetyl]amino]-methyl]-7-oxabicyclo[2.2.1]hept-2- yl]-5-heptenoic acid [-)-7) was found to be a potent and selective thromboxane A2 (TxA2) receptor antagonist. Unlike the related series of omega-chain allylic alcohols, amide 7 and its congeners were uniformly free of direct contractile activity in vitro (bovine coronary) and in vivo (anesthetized guinea pig). Amide 7 was effective in the inhibition of (a) arachidonic acid induced platelet aggregation of human platelet-rich plasma (I50 = 0.18 +/- 0.006 microM), (b) 11,9-epoxymethano-PGH2 induced platelet aggregation of human platelet-rich plasma (I50 = 0.24 microM), (c) 11,9-epoxymethano-PGH2 induced contraction of guinea pig trachea (Kb = 3.0 +/- 0.3 nM) or rat aorta (Kb = 8.8 +/- 1.1 nM), and (d) arachidonic acid induced bronchoconstriction in the anesthetized guinea pig (0.1-1.0 mg/kg iv). Amide 7 inhibited the binding of [5,6-3H2]-[1S- (1 alpha, 2 alpha (Z), 3 alpha, 4 alpha)]-7-[3-[[2-[(Phenyl- amino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic acid to human platelet membranes in a specific and saturable manner with a Kd = 49.6 +/- 1.4 nM.

摘要

一种新型双环前列腺素类似物，[1S-[1α,2α(Z),3α,4α]]-7-[3-[[[[(1-氧代庚基)氨基]乙酰基]氨基]-甲基]-7-氧杂双环[2.2.1]庚-2-基]-5-庚烯酸[(-)-7]被发现是一种强效且选择性的血栓素A2（TxA2）受体拮抗剂。与相关的ω-链烯丙醇系列不同，酰胺7及其同系物在体外（牛冠状动脉）和体内（麻醉的豚鼠）均无直接收缩活性。酰胺7可有效抑制：(a) 花生四烯酸诱导的人富含血小板血浆的血小板聚集（I50 = 0.18 ± 0.006 μM）；(b) 11,9-环氧甲撑-PGH2诱导的人富含血小板血浆的血小板聚集（I50 = 0.24 μM）；(c) 11,9-环氧甲撑-PGH2诱导的豚鼠气管收缩（Kb = 3.0 ± 0.3 nM）或大鼠主动脉收缩（Kb = 8.8 ± 1.1 nM）；以及(d) 花生四烯酸诱导的麻醉豚鼠的支气管收缩（静脉注射0.1 - 1.0 mg/kg）。酰胺7以特异性和饱和性方式抑制[5,6-3H2]-[1S-(1α,2α(Z),3α,4α)]-7-[3-[[2-[(苯基-氨基)羰基]肼基]甲基]-7-氧杂双环[2.2.1]庚-2-基]-5-庚烯酸与人血小板膜的结合，Kd = 49.6 ± 1.4 nM。