Design, synthesis, and structure-activity relationship studies of novel 1-[(1-Acyl-4-piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives as potent, orally active platelet-activating factor antagonists

被引:22
作者
Carceller, E
Merlos, M
Giral, M
Balsa, D
GarciaRafanell, J
Forn, J
机构
[1] Research Center, J. Uriach and Cía. S.A., 08026 Barcelona
关键词
D O I
10.1021/jm950555i
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Replacement of the polar head of our previous series of 1-acyl-4-[(2-methyl-3-pyridyl)-cyanomethyl]piperazines with a 2-methylimidazo[4,5-c]pyridine group has led to the identification of a new series of 1-[(1-acyl-4-piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives as potent, orally active platelet-activating factor (PAF) antagonists. On the basis of the general structure-activity relationship trends found for the acyl substituent in our earlier series, five groups of compounds were tested, diaryl- or alkylarylpropanoyl derivatives, their 3-hydroxy-substituted analogues, and urea, carbamate and amino acid derivatives. The optimal compound 19 (UR-12670), bearing the 3,3-diphenylpropanoyl moiety, exhibited very high in vitro and in vivo potency (IC50 = 0.0076 mu M for the in vitro PAF-induced platelet aggregation assay, ID50 = 0.0086 mg/kg for the in vivo PAF-induced hypotension test in normotensive rats, and ID50 = 0.092 mg/kg po and 0.0008 mg/kg iv for the PAF-induced mortality test in mice). Compound 19 also showed long duration of activity. It gave 100% protection against PAF-induced mortality in mice 7 h after iv administration of a single dose of 1 mg/kg and also provided 100% inhibition of PAF-induced aggregation in dog whole blood 6 h after iv administration of the same dose. The lead structure 19 has been selected for in-depth pharmacological evaluation.
引用
收藏
页码:487 / 493
页数:7
相关论文
共 17 条
[1]   THE EFFECTS OF PAF-ACETHER ON THE CARDIOVASCULAR-SYSTEM AND THEIR INHIBITION BY A NEW HIGHLY SPECIFIC PAF-ACETHER RECEPTOR ANTAGONIST BN 52021 [J].
BARANES, J ;
HELLEGOUARCH, A ;
LEHEGARAT, M ;
VIOSSAT, I ;
AUGUET, M ;
CHABRIER, PE ;
BRAQUET, P ;
BRAQUET, F .
PHARMACOLOGICAL RESEARCH COMMUNICATIONS, 1986, 18 (08) :717-737
[2]   AGGREGATION OF BLOOD PLATELETS BY ADENOSINE DIPHOSPHATE AND ITS REVERSAL [J].
BORN, GVR .
NATURE, 1962, 194 (4832) :927-&
[3]   (PYRIDYLCYANOMETHYL)PIPERAZINES AS ORALLY ACTIVE PAF ANTAGONISTS [J].
CARCELLER, E ;
ALMANSA, C ;
MERLOS, M ;
GIRAL, M ;
BARTROLI, J ;
GARCIARAFANELL, J ;
FORN, J .
JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (22) :4118-4134
[4]   SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 1-ACYL-4-((2-METHYL-3-PYRIDYL)CYANOMETHYL)PIPERAZINES AS PAF ANTAGONISTS [J].
CARCELLER, E ;
MERLOS, M ;
GIRAL, M ;
ALMANSA, C ;
BARTROLI, J ;
GARCIARAFANELL, J ;
FORN, J .
JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (20) :2984-2997
[5]   ELECTRONIC AGGREGOMETER - NOVEL DEVICE FOR ASSESSING PLATELET BEHAVIOR IN BLOOD [J].
CARDINAL, DC ;
FLOWER, RJ .
JOURNAL OF PHARMACOLOGICAL METHODS, 1980, 3 (02) :135-158
[6]   PHARMACOLOGICAL MODULATION OF PAF-INDUCED MORTALITY IN MICE [J].
CARLSON, RP ;
ONEILLDAVIS, L ;
CHANG, J .
AGENTS AND ACTIONS, 1987, 21 (3-4) :379-381
[7]  
GOLDING BT, 1977, SYNTHESIS-STUTTGART, P423
[8]   A PARTIAL PHARMACOPHORE FOR THE PLATELET-ACTIVATING-FACTOR (PAF) RECEPTOR [J].
HODGKIN, EE ;
MILLER, A ;
WHITTAKER, M .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1992, 2 (06) :597-602
[9]   POTENTIAL INHIBITORS OF S-ADENOSYLMETHIONINE-DEPENDENT METHYLTRANSFERASES .8. MOLECULAR DISSECTIONS OF CARBOCYCLIC 3-DEAZAADENOSINE AS INHIBITORS OF S-ADENOSYLHOMOCYSTEINE HYDROLASE [J].
HOUSTON, DM ;
DOLENCE, EK ;
KELLER, BT ;
PATELTHOMBRE, U ;
BORCHARDT, RT .
JOURNAL OF MEDICINAL CHEMISTRY, 1985, 28 (04) :467-471
[10]  
NIELSEN OBT, 1973, J MED CHEM, V16, P1170