Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration

Christopher J Lunniss; Anthony W J Cooper; Colin D Eldred; Michael Kranz; Mika Lindvall; Fiona S Lucas; Margarete Neu; Alex G S Preston; Lisa E Ranshaw; Alison J Redgrave; J Ed Robinson; Tracy J Shipley; Yemisi E Solanke; Don O Somers; Joanne O Wiseman

doi:10.1016/j.bmcl.2009.01.045

Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1380-5. doi: 10.1016/j.bmcl.2009.01.045. Epub 2009 Jan 19.

Authors

Christopher J Lunniss¹, Anthony W J Cooper, Colin D Eldred, Michael Kranz, Mika Lindvall, Fiona S Lucas, Margarete Neu, Alex G S Preston, Lisa E Ranshaw, Alison J Redgrave, J Ed Robinson, Tracy J Shipley, Yemisi E Solanke, Don O Somers, Joanne O Wiseman

Affiliation

¹ GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, England.

PMID: 19195882
DOI: 10.1016/j.bmcl.2009.01.045

Abstract

Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.

Publication types

Comparative Study

MeSH terms

Administration, Oral
Animals
Cattle
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
Humans
Male
Phosphodiesterase 4 Inhibitors*
Phosphodiesterase Inhibitors / administration & dosage*
Phosphodiesterase Inhibitors / chemistry*
Protein Structure, Secondary
Protein Structure, Tertiary
Quinolines / administration & dosage*
Quinolines / chemistry*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Phosphodiesterase 4 Inhibitors
Phosphodiesterase Inhibitors
Quinolines
Cyclic Nucleotide Phosphodiesterases, Type 4