Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors.
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.
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
Chiara
C
Brullo
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
Matteo
M
Massa
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
Carla
C
Villa
Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Via LB Alberti, 2, 16132 Genoa, Italy.
Roberta
R
Ricciarelli
Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Via LB Alberti, 2, 16132 Genoa, Italy.
Daniela
D
Rivera
Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Via LB Alberti, 2, 16132 Genoa, Italy.
Maria Adelaide
MA
Pronzato
Department of Pharmacy, Section of Pharmacology and Toxicology, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Cembrano, 4, 16147 Genoa, Italy.
Ernesto
E
Fedele
Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
Elisabetta
E
Barocelli
Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
Simona
S
Bertoni
Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
Lisa
L
Flammini
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.
Olga
O
Bruno
D000818:Animals; D002396:Catechols / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism*; D003975:Diazepam / Q000097:blood / Q000493:pharmacokinetics; D057075:Enzyme Assays; D015870:Gene Expression; D054879:Halogenation; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018697:Nootropic Agents / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D020889:Rolipram / Q000097:blood / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D002396:Catechols; D007527:Isoenzymes; D018697:Nootropic Agents; D010726:Phosphodiesterase Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human; D020889:Rolipram; D003975:Diazepam
Microwave-assisted reaction; PDE4D; Pharmacokinetic properties; Phosphodiesterases type 4D inhibitors; cAMP enhancers