Orally active indole N-oxide PDE4 inhibitors

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

doi:10.1016/s0960-894x(98)00572-1

Orally active indole N-oxide PDE4 inhibitors

Bioorg Med Chem Lett. 1998 Nov 3;8(21):3053-8. doi: 10.1016/s0960-894x(98)00572-1.

Authors

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

Affiliation

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

PMID: 9873675
DOI: 10.1016/s0960-894x(98)00572-1

Abstract

This communication describes the synthesis and in vitro and in vivo evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. Several of the compounds presented possess low nanomolar IC50's for PDE4 inhibition and excellent in vivo activity for inhibition of TNF-alpha levels in LPS challenged mice (mouse endotoxemia model). Emesis studies (dog) and efficacy in a SCW arthritis model for the most potent PDE4 inhibitors are presented.

MeSH terms

3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
Administration, Oral
Animals
Arthritis, Infectious / drug therapy
Cyclic Nucleotide Phosphodiesterases, Type 4
Dogs
Female
Indoles / chemical synthesis*
Indoles / pharmacology
Mice
Mice, Inbred BALB C
Phosphodiesterase Inhibitors / chemical synthesis*
Phosphodiesterase Inhibitors / pharmacokinetics
Tumor Necrosis Factor-alpha / antagonists & inhibitors*

Substances

Indoles
Phosphodiesterase Inhibitors
Tumor Necrosis Factor-alpha
3',5'-Cyclic-AMP Phosphodiesterases
Cyclic Nucleotide Phosphodiesterases, Type 4