The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I

C Hulme; K Moriarty; B Miller; R Mathew; M Ramanjulu; P Cox; J Souness; K M Page; J Uhl; J Travis; F C Huang; R Labaudiniere; S W Djuric

doi:10.1016/s0960-894x(98)00324-2

The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I

Bioorg Med Chem Lett. 1998 Jul 21;8(14):1867-72. doi: 10.1016/s0960-894x(98)00324-2.

Authors

C Hulme¹, K Moriarty, B Miller, R Mathew, M Ramanjulu, P Cox, J Souness, K M Page, J Uhl, J Travis, F C Huang, R Labaudiniere, S W Djuric

Affiliation

¹ Rhône-Poulenc Rorer Central Research, Collegeville, PA 19426, USA.

PMID: 9873449
DOI: 10.1016/s0960-894x(98)00324-2

Abstract

This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds described contain an indole moiety which replaces the 'rolipram-like' 3-methoxy-4-cyclopentoxy motif. Several of the compounds presented possess low nanomolar IC50's for PDEIV inhibition. In vivo activities determined from measurement of serum TNF-alpha levels in LPS challenged mice (mouse endotoxemia model) are also reported.

MeSH terms

3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
Animals
Biological Availability
Cyclic Nucleotide Phosphodiesterases, Type 4
Drug Evaluation
Indoles / chemical synthesis*
Indoles / pharmacokinetics
Indoles / pharmacology*
Mice
Phosphodiesterase Inhibitors / chemical synthesis*
Phosphodiesterase Inhibitors / pharmacokinetics
Phosphodiesterase Inhibitors / pharmacology*
Pyrrolidinones / pharmacology
Rolipram
Structure-Activity Relationship

Substances

Indoles
Phosphodiesterase Inhibitors
Pyrrolidinones
3',5'-Cyclic-AMP Phosphodiesterases
Cyclic Nucleotide Phosphodiesterases, Type 4
Rolipram