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

Chiara Brullo; Matteo Massa; Carla Villa; Roberta Ricciarelli; Daniela Rivera; Maria Adelaide Pronzato; Ernesto Fedele; Elisabetta Barocelli; Simona Bertoni; Lisa Flammini; Olga Bruno

doi:10.1016/j.bmc.2015.04.027

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

Bioorg Med Chem. 2015 Jul 1;23(13):3426-35. doi: 10.1016/j.bmc.2015.04.027. Epub 2015 Apr 16.

Authors

Affiliations

¹ Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
² Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Via LB Alberti, 2, 16132 Genoa, Italy.
³ Department of Pharmacy, Section of Pharmacology and Toxicology, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Cembrano, 4, 16147 Genoa, Italy.
⁴ Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
⁵ Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy. Electronic address: obruno@unige.it.

PMID: 25936260
DOI: 10.1016/j.bmc.2015.04.027

Abstract

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.

Keywords: Microwave-assisted reaction; PDE4D; Pharmacokinetic properties; Phosphodiesterases type 4D inhibitors; cAMP enhancers.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Catechols / blood
Catechols / chemical synthesis
Catechols / pharmacokinetics*
Cell Line, Tumor
Cell Survival / drug effects
Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
Diazepam / blood
Diazepam / pharmacokinetics
Enzyme Assays
Gene Expression
Halogenation
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / chemistry
Isoenzymes / metabolism
Male
Mice
Mice, Inbred BALB C
Motor Activity / drug effects
Neurons / cytology
Neurons / drug effects*
Neurons / enzymology
Nootropic Agents / blood
Nootropic Agents / chemical synthesis
Nootropic Agents / pharmacokinetics*
Phosphodiesterase Inhibitors / blood
Phosphodiesterase Inhibitors / chemical synthesis
Phosphodiesterase Inhibitors / pharmacokinetics*
Rolipram / blood
Rolipram / pharmacokinetics
Structure-Activity Relationship

Substances

Catechols
Isoenzymes
Nootropic Agents
Phosphodiesterase Inhibitors
Cyclic Nucleotide Phosphodiesterases, Type 4
PDE4D protein, human
Rolipram
Diazepam