Synthesis and Pharmacological Characterization of Novel Druglike Corticotropin-Releasing Factor 1 Antagonists

被引：30

作者：

Di Fabio, Romano ^{[1
]}

St-Denis, Yves ^{[1
]}

Sabbatini, Fabio M. ^{[1
]}

Andreotti, Daniele ^{[1
]}

Arban, Roberto ^{[1
]}

Bernasconi, Giovanni ^{[1
]}

Braggio, Simone ^{[1
]}

Blaney, Frank E. ^{[5
]}

Capelli, Anna M. ^{[3
]}

Castiglioni, Emiliano ^{[1
]}

Di Modugno, Enza ^{[4
]}

Donati, Daniele ^{[1
]}

Fazzolari, Elettra ^{[1
]}

Ratti, Emiliangelo ^{[1
]}

Feriani, Aldo ^{[3
]}

Contini, Stefania ^{[1
]}

Gentile, Gabriella ^{[1
]}

Ghirlanda, Damiano ^{[1
]}

Provera, Stefano ^{[2
]}

Marchioro, Carla ^{[2
]}

Roberts, Karen L. ^{[1
]}

Mingardi, Anna ^{[1
]}

Mattioli, Mario ^{[1
]}

Nalin, Arnaldo ^{[1
]}

Pavone, Francesca ^{[1
]}

Spada, Simone ^{[1
]}

Trist, David G. ^{[1
]}

Worby, Angela ^{[6
]}

机构：

[1] GlaxoSmithKline Med Res Ctr, Neurosci Ctr Excellence Drug Discovery, I-37135 Verona, Italy

[2] GlaxoSmithKline Med Res Ctr, Mol Discovery Res, Analyt Chem, I-37135 Verona, Italy

[3] GlaxoSmithKline Med Res Ctr, Mol Discovery Res Computat & Struct Sci, I-37135 Verona, Italy

[4] GlaxoSmithKline Med Res Ctr, Global Project Management, I-37135 Verona, Italy

[5] GlaxoSmithKline New Frontiers Sci Pk, Mol Discovery Res Computat & Struct Sci, Harlow, Essex, England

[6] New Frontiers Sci Pk, Dept Screening & Compound Profiling, Mol Discovery Res, Harlow, Essex, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 23期

关键词：

D O I：

10.1021/jm800744m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To identify new CRF1 receptor antagonists, an attempt to modify the bis-hetherocycle moiety present in the top region of the dihydropirrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF1 receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic hetherocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.

引用

页码：7370 / 7379

页数：10

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