Synthesis and Evaluation as PDE4 Inhibitors of Pyrimidine-2,4-dione Derivatives

被引：3

作者：

Giovannoni, Maria P. ^{[1
]}

Graziano, Alessia ^{[1
]}

Matucci, Rosanna ^{[2
]}

Nesi, Marta ^{[2
]}

Cesari, Nicoletta ^{[1
]}

Vergelli, Claudia ^{[1
]}

Biancalani, Claudio ^{[1
]}

Crocetti, Letizia ^{[1
]}

Cilibrizzi, Agostino ^{[1
]}

Dal Piaz, Vittorio ^{[1
]}

机构：

[1] Dipartimento Sci Farmaceut, I-50019 Florence, Italy

[2] Dipartimento Farmacol Preclin & Clin MA Mancini, Florence, Italy

来源：

DRUG DEVELOPMENT RESEARCH | 2011年 / 72卷 / 03期

关键词：

HARBS; PDE4; selectivity; CROSS-COUPLING REACTIONS; PHOSPHODIESTERASE-4; INHIBITORS; C-N; POTENT; ROLIPRAM; BINDING; SUPPRESSION; THALIDOMIDE; EXPRESSION; ANALOGS;

D O I：

10.1002/ddr.20395

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of nitraquazone analogs with a pyrimidindione core was synthesized and tested for inhibitory activity on PDE4, selectivity versus PDE3 and PDE5 and for affinity towards the rolipram high-affinity binding site (HARBS). The 5-anilino derivatives 13-18 showed the best profile combining appreciable PDE4 inhibitory activity (IC50 = 5-14 mu M) with a good selectivity toward PDE3 and PDE5. The same compounds demonstrate low affinity for the HARBS site with IC50 values of 12-69 mu M (IC50 for Rolipram = 3.6 nM). Drug Dev Res 72:274-288, 2011. (C) 2010 Wiley-Liss, Inc.

引用

页码：274 / 288

页数：15

共 52 条

[1]

Barnette MS, 1998, J PHARMACOL EXP THER, V284, P420

[2]

BAYES M, 2007, METHOD FIND EXP CLIN, V9, P467

[3] OPC-6535, a superoxide anion production inhibitor, attenuates acute lung injury [J].

Bloomfield, GL ;

Ridings, PC ;

Blocher, CR ;

Fisher, BJ ;

Sugerman, HJ ;

Nagamoto, H ;

Fowler, AA .

JOURNAL OF SURGICAL RESEARCH, 1997, 72 (01) :70-77

[4]

BORMANN G, 1981, Patent No. 2477148

[5]

BRADFORD MM, 1976, ANAL BIOCHEM, V127, P105

[6] Polymer-supported copper complex for C-N and C-O cross-coupling reactions with aryl boronic acids [J].

Chiang, GCH ;

Olsson, T .

ORGANIC LETTERS, 2004, 6 (18) :3079-3082

[7] 1,4-cyclohexanecarboxylates: Potent and selective inhibitors of phosphodiesterase 4 for the treatment of asthma [J].

Christensen, SB ;

Guider, A ;

Forster, CJ ;

Gleason, JG ;

Bender, PE ;

Karpinski, JM ;

DeWolf, WE ;

Barnette, MS ;

Underwood, DC ;

Griswold, DE ;

Cieslinski, LB ;

Burman, M ;

Bochnowicz, S ;

Osborn, RR ;

Manning, CD ;

Grous, M ;

Hillegas, LM ;

Bartus, JO ;

Ryan, MD ;

Eggleston, DS ;

Haltiwanger, RC ;

Torphy, TJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (06) :821-835

[8]

Dal Piaz V, 1998, EUR J MED CHEM, V33, P789

[9] Phosphodiesterase 4 inhibitors, structurally unrelated to Rolipram, as promising agents for the treatment of asthma and other pathologies [J].

Dal Piaz, V ;

Giovannoni, MP .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2000, 35 (05) :463-480

[10] Novel heterocyclic-fused pyridazinones as potent and selective phosphodiesterase IV inhibitors [J].

DalPiaz, V ;

Giovannoni, MP ;

Castellana, C ;

Palacios, JM ;

Beleta, J ;

Domenech, T ;

Segarra, V .

JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (10) :1417-1421

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