Synthesis, Biological Evaluation, and Molecular Modeling of New 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-Dimethylmorpholino)-2-oxoethyl) Oxime (GEBR-7b) Related Phosphodiesterase 4D (PDE4D) Inhibitors

被引：18

作者：

Brullo, Chiara ^{[1
]}

Massa, Matteo ^{[1
]}

Rocca, Massimo ^{[1
]}

Rotolo, Chiara ^{[1
]}

Guariento, Sara ^{[1
]}

Rivera, Daniela ^{[2
]}

Ricciarelli, Roberta ^{[2
]}

Fedele, Ernesto ^{[3
]}

Fossa, Paola ^{[1
]}

Bruno, Olga ^{[1
]}

机构：

[1] Univ Genoa, Sch Med & Pharmaceut Sci, Dept Pharm, Med Chem Sect, I-16132 Genoa, Italy

[2] Univ Genoa, Sch Med & Pharmaceut Sci, Dept Expt Med, Sect Gen Pathol, I-16132 Genoa, Italy

[3] Univ Genoa, Sch Med & Pharmaceut Sci, Dept Pharm, Sect Pharmacol & Toxicol, I-16147 Genoa, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 16期

关键词：

MOUSE MODEL; MEMORY; CAMP; ANTIDEPRESSANT; IMPROVEMENT; COGNITION; ROLIPRAM; TARGETS; PROTEIN; DESIGN;

D O I：

10.1021/jm500855w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new series of 3-(cyclopentyloxy)-4-methoxyphenyl derivatives, structurally related to our hit GEBR-4a (1) and GEBR-7b (2), has been designed by changing length and functionality of the chain linking the catecholic moiety to the terminal cycloamine portion. Among the numerous molecules synthesized, compounds 8, 10a, and 10b showed increased potency as PDE4D enzyme inhibitors with respect to 2 and a good selectivity against PDE4A4, PDE4B2, and PDE4C2 enzymes, without both cytotoxic and genotoxic effects. The ability to enhance cAMP level in neuronal cells was assessed for compound 8. SAR considerations, also confirmed by in silico docking simulations, evidenced that both chain and amino terminal function characterized by higher hydrophilicity are required for a good and selective inhibitor-catalytic pocket interaction.

引用

页码：7061 / 7072

页数：12

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