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Design, synthesis, and biological activities of new thieno[3,2-d] pyrimidines as selective type 4 phosphodiesterase inhibitors.

Abstract：

:A common pharmacophore for compounds structurally related to nitraquazone has been derived. Using this pharmacophore, new structures have been designed, synthesized, and evaluated for their inhibitory potencies against cyclic adenosine 5'-monophosphate (cAMP) specific phosphodiesterase (PDE 4). From these compounds, 4-benzylamino-2-butylthieno[3,2-d]pyrimidine (4) was selected for optimization. The effects of changes to the lipophilic groups and the amino linkage on the PDE 4 activity have been investigated. As a result, some potent PDE 4 inhibitors, selective with respect to PDE 3, have been identified. A selected group of compounds have been further evaluated for their ability to displace [3H]rolipram from its binding site and also to potentiate isoprenaline-induced cAMP accumulation in isolated guinea pig eosinophils. Of these, 2-butyl-4-cyclohexylaminothieno[3,2-d]pyrimidine (33) has an interesting profile, with an important improvement in PDE 4/[3H]rolipram ratio with respect to reference drugs, and good activity in cAMP potentiation, consistent with efficient cell penetration.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Crespo MI,Pagès L,Vega A,Segarra V,López M,Doménech T,Miralpeix M,Beleta J,Ryder H,Palacios JM

doi

10.1021/jm981012m

subject

Has Abstract

pub_date

1998-10-08 00:00:00

pages

4021-35

issue

21

eissn

0022-2623

issn

1520-4804

pii

jm981012m

journal_volume

41

pub_type

杂志文章

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