Synthesis, antiplatelet activity and comparative molecular field analysis of substituted 2-amino4H-pyrido[1,2-a]pyrimidin-4-ones, their congeners and isosteric analogues

被引:42
作者
Roma, G
Cinone, N
Di Braccio, M
Grossi, G
Leoncini, G
Signorello, MG
Carott, A
机构
[1] Univ Genoa, Dipartimento Sci Farmaceut, I-16132 Genoa, Italy
[2] Univ Genoa, Sezione Biochim, Dipartimento Med Sperimentale, I-16132 Genoa, Italy
[3] Univ Bari, Dipartimento Farmacochim, I-70125 Bari, Italy
关键词
D O I
10.1016/S0968-0896(00)00010-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
2-(1-Piperazinyl)-4H-pyrido[1,2-a]pyrimidin-4-one (5a) is a recently described in vitro inhibitor of human platelet aggregation which specifically inhibits the activity of high affinity cAMP phosphodiesterase. A number of substitution derivatives, isosteres, and analogues of 5a were now synthesized and tested in vitro for their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen, or the Ca2+ ionophore A23187. Among the most effective compounds, the 6-methyl, 8-methyl and 6,8-dimethyl derivatives of 5a resulted nearly as active as the lead when platelet aggregation was induced by ADP or A23187, but less active when collagen was the inducer. On the basis of present results and those previously obtained by us in this and 2-aminochromone structural fields, we have developed a statistically significant 3-D QSAR model, using comparative molecular field analysis (CoMFA), describing the variation of the antiplatelet activity in terms of molecular steric and electrostatic potential changes. (C) 2000 Elsevier Science Ltd. All rights reserved.
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收藏
页码:751 / 768
页数:18
相关论文
共 31 条
[11]  
ERMILI A, 1971, GAZZ CHIM ITAL, V101, P269
[12]  
ERMILI A, 1976, FARMACO-ED SCI, V31, P627
[13]  
ERMILI A, 1977, FARMACO-ED SCI, V32, P375
[14]  
ERMILI A, 1977, FARMACO-ED SCI, V32, P713
[15]  
ERMILI A, 1971, GAZZ CHIM ITAL, V101, P651
[16]   MOLECULAR LIPOPHILICITY POTENTIAL, A TOOL IN 3D QSAR - METHOD AND APPLICATIONS [J].
GAILLARD, P ;
CARRUPT, PA ;
TESTA, B ;
BOUDON, A .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 1994, 8 (02) :83-96
[17]   ALKYLATION STUDIES ON 6-ETHYL-2,3-DIHYDROTHIAZOLO-[3,2-A]PYRIMIDINE-5,7-DIONES [J].
GLENNON, RA ;
BASS, RG ;
SCHUBERT, E .
JOURNAL OF HETEROCYCLIC CHEMISTRY, 1979, 16 (05) :903-907
[18]   CHEMISTRY OF PYRIDO[1,2-ALPHA]PYRIMIDINES [J].
HERMECZ, I ;
MESZAROS, Z .
ADVANCES IN HETEROCYCLIC CHEMISTRY, 1983, 33 :241-330
[19]  
HERMECZ I, 1984, SYNTHESIS-STUTTGART, P152
[20]   PREPARATION STRUCTURE AND REACTIONS OF SOME MALONYL-ALPHA-AMINOPYRIDINES [J].
INGALLS, EA ;
POPP, FD .
JOURNAL OF HETEROCYCLIC CHEMISTRY, 1967, 4 (04) :523-&