Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors

被引：16

作者：

Brullo, Chiara ^{[1
]}

Massa, Matteo ^{[1
]}

Villa, Carla ^{[1
]}

Ricciarelli, Roberta ^{[2
]}

Rivera, Daniela ^{[2
]}

Pronzato, Maria Adelaide ^{[2
]}

Fedele, Ernesto ^{[3
]}

Barocelli, Elisabetta ^{[4
]}

Bertoni, Simona ^{[4
]}

Flammini, Lisa ^{[4
]}

Bruno, Olga ^{[1
]}

机构：

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

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

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

[4] Univ Parma, Dept Pharm, I-43124 Parma, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 13期

关键词：

Phosphodiesterases type 4D inhibitors; PDE4D; cAMP enhancers; Pharmacokinetic properties; Microwave-assisted reaction; ANTIDEPRESSANT-LIKE; MOUSE MODEL; KNOCK-DOWN; MEMORY; PHOSPHODIESTERASE-4; ROLIPRAM; CAMP; IMPROVEMENT; COGNITION; GEBR-7B;

D O I：

10.1016/j.bmc.2015.04.027

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：3426 / 3435

页数：10

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