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

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Brullo C,Massa M,Villa C,Ricciarelli R,Rivera D,Pronzato MA,Fedele E,Barocelli E,Bertoni S,Flammini L,Bruno O

doi

10.1016/j.bmc.2015.04.027

subject

Has Abstract

pub_date

2015-07-01 00:00:00

pages

3426-35

issue

13

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(15)00325-9

journal_volume

23

pub_type

杂志文章

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