Synthesis of (E)-8-(3-Chlorostyryl)caffeine Analogues Leading to 9-Deazaxanthine Derivatives as Dual A2A Antagonists/MAO-B Inhibitors

被引：47

作者：

Rivara, Silvia ^{[1
]}

Piersanti, Giovanni ^{[2
]}

Bartoccini, Francesca ^{[2
]}

Diamantini, Giuseppe ^{[2
]}

Pala, Daniele ^{[1
]}

Riccioni, Teresa ^{[3
]}

Stasi, Maria Antonietta ^{[3
]}

Cabri, Walter ^{[3
]}

Borsini, Franco ^{[3
]}

Mor, Marco ^{[1
]}

Tarzia, Giorgio ^{[2
]}

Minetti, Patrizia ^{[3
]}

机构：

[1] Univ Parma, Dipartimento Farm, I-43124 Parma, Italy

[2] Univ Urbino, Dept Biomol Sci, I-61029 Urbino, PU, Italy

[3] Sigma Tau Ind Farmaceut Riunite SpA, I-00040 Pomezia, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 03期

关键词：

ADENOSINE RECEPTOR ANTAGONISTS; MONOAMINE-OXIDASE-B; PARKINSONS-DISEASE; ARYL IODIDES; COUPLING REACTIONS; CROSS-COUPLINGS; SCH; 58261; C-C; POTENT; ST1535;

D O I：

10.1021/jm301686s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A systematic modification of the caffeinyl core and substituents of the reference compound (E)-8-(3-chlorostyryl)caffeine led to the 9-deazaxanthine derivative (E)-6-(4-chlorostyryl)-1,3,5,=trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-(3H,5H)-dione (17f), which acts as a dual human A(2a) antagonist/MAO-B inhibitor (K-i(A(2A)) = 260 nM; IC50(MAO-B) = 200 nM; IC50(MAO-A) = 10 mu M) and dose dependently counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by the oral route. The compound is the best balanced A(2A) antagonist/MAO-B inhibitor reported to date, and it could be considered as a new lead in the field of anti-Parkinson's agents. A number of analogues of 17f were synthesized and qualitative SARs are discussed. Two analogues of 17f, namely 18b and 19a, inhibit MAO-B with IC50 of 68 and 48 nM, respectively, being 5-7-fold more potent than the prototypical MAO-B inhibitor deprenyl (IC50 = 334 nM).

引用

页码：1247 / 1261

页数：15

共 88 条

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