SYNTHESIS AND INVITRO ACTIVITY OF STEREOISOMERS OF A NOVEL THROMBOXANE RECEPTOR ANTAGONIST, (+/-)-(5Z)-7-[3-ENDO-[(PHENYLSULFONYL)AMINO]BICYCLO[2.2.1]HEPT-2-EXO-YL]HEPTENOIC ACID

被引:26
作者
OHTANI, M
NARISADA, M
机构
[1] Shionogi Research Laboratories, Shionogi & Co., Ltd, Osaka 553, Fukushima-ku
关键词
D O I
10.1021/jm00165a022
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Three stereoisomers of S-145 (1) with variations at the side-chain junctions were synthesized. Endo-cis isomer 10 and N-exo-trans isomer 18 were obtained via the common intermediate 5 having an endo-fused ring structure. Exocis isomer 28 was prepared via exo-fused azetidino compound 21. Inhibitory concentrations (IC50) of the sodium salts newly obtained for platelet aggregation were measured using washed rat platelets (WP) and human platelet-rich plasma (PRP). The IC50 values of these compounds for contraction of the rat aorta were also measured. Compound 1 of N-endo-trans structure and N-exo-trans isomer 18 exhibited more potent inhibitory activity than cis-isomers 10 and 28 against responses induced by TXA2-related substances for rat WP and rat thoracic aorta. However, these compounds exhibited almost comparable inhibitory activity for human PRP. © 1990, American Chemical Society. All rights reserved.
引用
收藏
页码:1027 / 1031
页数:5
相关论文
共 27 条
[1]   THROMBOXANE INDUCED RED-BLOOD-CELL LYSIS [J].
BREZINSKI, ME ;
LEFER, DJ ;
BOWKER, B ;
LEFER, AM .
PROSTAGLANDINS, 1987, 33 (01) :75-84
[2]   CARDIOPROTECTIVE ACTIONS OF SPECIFIC THROMBOXANE RECEPTOR ANTAGONIST IN ACUTE MYOCARDIAL-ISCHEMIA [J].
BREZINSKI, ME ;
YANAGISAWA, A ;
LEFER, AM .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1987, 9 (01) :65-71
[3]   CONVENIENT SYNTHETIC ROUTES TO 5,6-TRIMETHYLENENORBORNANONES [J].
BROWN, HC ;
ROTHBERG, I ;
VANDERJA.DL .
JOURNAL OF ORGANIC CHEMISTRY, 1972, 37 (25) :4098-4100
[4]  
BUNDY G L, 1975, Tetrahedron Letters, V24, P1957
[5]   COMPARISON OF THE ACTIONS OF U-46619, A PROSTAGLANDIN H2-ANALOGUE, WITH THOSE OF PROSTAGLANDIN-H2 AND THROMBOXANE-A2 ON SOME ISOLATED SMOOTH-MUSCLE PREPARATIONS [J].
COLEMAN, RA ;
HUMPHREY, PPA ;
KENNEDY, I ;
LEVY, GP ;
LUMLEY, P .
BRITISH JOURNAL OF PHARMACOLOGY, 1981, 73 (03) :773-778
[6]   QUANTITATION OF DRUG LEVELS AND PLATELET RECEPTOR BLOCKADE CAUSED BY A THROMBOXANE ANTAGONIST [J].
FRIEDHOFF, LT ;
MANNING, J ;
FUNKE, PT ;
IVASHKIV, E ;
TU, J ;
COOPER, W ;
WILLARD, DA .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1986, 40 (06) :634-642
[7]   ACTIONS OF THE NOVEL THROMBOXANE A2 ANTAGONISTS, ONO-1270 AND ONO-3708, ON SMOOTH-MUSCLE CELLS OF THE GUINEA-PIG BASILAR ARTERY [J].
FUJIOKA, M ;
NAGAO, T ;
KURIYAMA, H .
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 1986, 334 (04) :468-474
[8]   9,11-EPOXY-9-HOMO-14-OXAPROSTA-5-ENOIC ACID-DERIVATIVES - NOVEL INHIBITORS OF FATTY-ACID CYCLOOXYGENASE [J].
HALL, SE ;
HAN, WC ;
HASLANGER, MF ;
HARRIS, DN ;
OGLETREE, ML .
JOURNAL OF MEDICINAL CHEMISTRY, 1986, 29 (11) :2335-2347
[9]  
HALUSHKA PV, 1987, FASEB J, V46, P149
[10]   BIOCHEMICAL-CHARACTERIZATION AND COMPARISON OF RAT THROMBOXANE-A2 PROSTAGLANDIN-H2 RECEPTORS IN PLATELETS AND CULTURED AORTIC SMOOTH-MUSCLE CELLS [J].
HANASAKI, K ;
NAKANO, K ;
KASAI, H ;
ARITA, H .
BIOCHEMICAL PHARMACOLOGY, 1989, 38 (18) :2967-2976