5-HT3 RECEPTOR ANTAGONISTS .2. 4-HYDROXY-3-QUINOLINECARBOXYLIC ACID-DERIVATIVES

被引:48
作者
HAYASHI, H [1 ]
MIWA, Y [1 ]
ICHIKAWA, S [1 ]
YODA, N [1 ]
MIKI, I [1 ]
ISHII, A [1 ]
KONO, M [1 ]
YASUZAWA, T [1 ]
SUZUKI, F [1 ]
机构
[1] KYOWA HAKKO KOGYO CO LTD,PHARMACEUT RES LABS,1188 SHIMOTOGARI,NAGAIZUMI,SHIZUOKA 411,JAPAN
关键词
D O I
10.1021/jm00057a011
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 4-hydroxy-3-quinolinecarboxylic acid derivatives (6) and 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid derivatives (7) were designed and synthesized as 5-HT3 receptor antagonists. Molecular modeling studies suggested that the 3-carbonyl moiety in 6 was almost coplanar to the plane of an aromaticring, but in 7 there was a 30-degrees deviation. 4-Hydroxy substitution in quinoline derivatives enhanced affinity for the 5-HT3 receptors, and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-4-hydroxy-3-quinolinecarboxamide (6f) exhibited the most potent activity in the Bezold-Jarisch (B-J) reflex test (ED50=0.1 mug/kg, iv) among quinoline derivatives 6. Although 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives (7a) exhibited higher affinity (e.g., 7d: K(i) = 0.48 nM) for the 5-HT3 receptors than ondansetron (K(i) = 7.6 nM) or granisetron (K(i) = 2.1 nM), these amides showed less potent activity in the B-J reflex test than the reference compounds. Interestingly, the ester derivatives 7c, 7f, and 7h eliminated affinity for the 5-HT3 receptors. These unusual structure-activity relationships and the deviation of the 3-carbonyl moiety from the plane of an aromatic ring suggest that the active conformation of 7a might be different from the proposed one for the preceding 5-HT3 antagonists. Thus, 6f was chosen for further studies. No receptor binding for a variety of ligands was significantly antagonized by 6f. Comparing the ratios of the ED50 value in the B-J reflex test (rat, iv) with the LD50 value in acute lethal toxicity (mouse, iv), 6f was proved to have a 600-fold wider margin of safety than ondansetron. Compound 6f dose-dependently attenuated both the incidence and frequency of emetic episodes induced by cisplatin in the dog (ED50 = 14 mug/kg, iv) more potently than ondansetron (ED50 = 210 mug/kg, iv). Compound 6f (KF-20170) is now under further investigation as a drug for treating gastrointestinal disorder.
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页码:617 / 626
页数:10
相关论文
共 52 条
[1]   DIRECT ACYLAMINATION OF 3-SUBSTITUTED PYRIDINE 1-OXIDES - DIRECTIVE EFFECT OF SUBSTITUENT [J].
ABRAMOVI.RA ;
ROGERS, RB .
JOURNAL OF ORGANIC CHEMISTRY, 1974, 39 (13) :1802-1807
[2]   CAMBRIDGE CRYSTALLOGRAPHIC DATA CENTER - COMPUTER-BASED SEARCH, RETRIEVAL, ANALYSIS AND DISPLAY OF INFORMATION [J].
ALLEN, FH ;
BELLARD, S ;
BRICE, MD ;
CARTWRIGHT, BA ;
DOUBLEDAY, A ;
HIGGS, H ;
HUMMELINK, T ;
HUMMELINKPETERS, BG ;
KENNARD, O ;
MOTHERWELL, WDS ;
RODGERS, JR ;
WATSON, DG .
ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE, 1979, 35 (OCT) :2331-2339
[3]  
[Anonymous], [No title captured]
[4]   3-ALPHA-(2-DIETHYLAMINOETHYL)-AMINOTROPANE AND RELATED COMPOUNDS [J].
ARCHER, S ;
LEWIS, TR ;
UNSER, MJ .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1957, 79 (15) :4194-4198
[5]   5-HYDROXYTRYPTAMINE (5-HT3) RECEPTOR ANTAGONISTS .1. INDAZOLE AND INDOLIZINE-3-CARBOXYLIC ACID-DERIVATIVES [J].
BERMUDEZ, J ;
FAKE, CS ;
JOINER, GF ;
JOINER, KA ;
KING, FD ;
MINER, WD ;
SANGER, GJ .
JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (07) :1924-1929
[6]   5-HYDROXYTRYPTAMINE (5-HT3) RECEPTOR ANTAGONISTS .2. 1-INDOLINECARBOXAMIDES [J].
BERMUDEZ, J ;
DABBS, S ;
JOINER, KA ;
KING, FD .
JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (07) :1929-1932
[7]  
BETBEDER D, 1988, Medical Science Research, V16, P141
[8]   NOVEL ANTAGONISTS OF THE 5-HT3 RECEPTOR - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF (2-ALKOXYBENZOYL) UREAS [J].
BRADLEY, G ;
WARD, TJ ;
WHITE, JC ;
COLEMAN, J ;
TAYLOR, A ;
RHODES, KF .
JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (09) :1515-1520
[9]   CHARMM - A PROGRAM FOR MACROMOLECULAR ENERGY, MINIMIZATION, AND DYNAMICS CALCULATIONS [J].
BROOKS, BR ;
BRUCCOLERI, RE ;
OLAFSON, BD ;
STATES, DJ ;
SWAMINATHAN, S ;
KARPLUS, M .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 1983, 4 (02) :187-217
[10]  
BUNCE K T, 1989, Gastroenterology, V96, pA64