Novel cyclic compounds as potent phosphodiesterase 4 inhibitors.

Journal of medicinal chemistry ·Vol. 41 ·No. 22 ·1998-10-22 ·Pages 4216-23

He W, Huang FC, Hanney B, Souness J, Miller B, Liang G, Mason J, Djuric S

Abstract

The synthesis and biological activity of a novel series of 2, 2-disubstituted indan-1,3-dione-based PDE4 inhibitors are described. This structurally unique class of PDE4 inhibitors is markedly different from the known PDE4 inhibitors such as RP 73401 (2) and CDP 840 (3). Structure-activity relationship (SAR) studies led to the identification of inhibitors with nanomolar potency and oral activity in a murine endotoxemia model for TNF-alpha inhibition. Unlike other classical PDE4 inhibitors, several analogues were found to be nonemetic in a canine emesis model at intravenous doses of up to 3 mg/kg.

MeSH Terms

3',5'-Cyclic-AMP Phosphodiesterases/metabolism Animals Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis,chemistry,pharmacology,toxicity Benzamides/chemical synthesis,chemistry,pharmacology,toxicity Brain/metabolism Cyclic Nucleotide Phosphodiesterases, Type 4 Dogs Endotoxemia/metabolism Female Guinea Pigs In Vitro Techniques Lipopolysaccharides/toxicity Macrophages, Peritoneal/drug effects,enzymology Male Mice Mice, Inbred BALB C Models, Molecular Phosphodiesterase Inhibitors/chemical synthesis,chemistry,pharmacology,toxicity Pyridines/chemical synthesis,chemistry,pharmacology,toxicity Structure-Activity Relationship Tumor Necrosis Factor-alpha/antagonists & inhibitors Vomiting/chemically induced

Chemicals

Anti-Inflammatory Agents, Non-Steroidal Benzamides Lipopolysaccharides Phosphodiesterase Inhibitors Pyridines Tumor Necrosis Factor-alpha CDP 840 3',5'-Cyclic-AMP Phosphodiesterases Cyclic Nucleotide Phosphodiesterases, Type 4 piclamilast

Authors & Affiliations

8 authors, click to expand affiliations / ORCID

He W

Department of Medicinal Chemistry, SW 8 Rhône-Poulenc Rorer Central Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA.

Huang F C

Hanney B

Souness J

Miller B

Liang G

Mason J

Djuric S

Article Info

Journal

Journal of medicinal chemistry

Abbr.

J Med Chem

ISSN

0022-2623

DOI

10.1021/jm970575f

Published

1998-10-22

Pages

4216-23

Language

English

Region

United States

NLM ID

9716531

Subset

External Links

PubMed source DOI: 10.1021/jm970575f View journal details

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Novel cyclic compounds as potent phosphodiesterase 4 inhibitors.

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