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

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 5; pp. 1380 - 1385
• Main Authors: Lunniss, Christopher J., Cooper, Anthony W.J., Eldred, Colin D., Kranz, Michael, Lindvall, Mika, Lucas, Fiona S., Neu, Margarete, Preston, Alex G.S., Ranshaw, Lisa E., Redgrave, Alison J., Ed Robinson, J., Shipley, Tracy J., Solanke, Yemisi E., Somers, Don O., Wiseman, Joanne O.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-03-2009
• Subjects: Administration, Oral; Animals; Cattle; COPD; Crystallography; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Humans; Male; PDE4; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors - administration & dosage; Phosphodiesterase Inhibitors - chemistry; Protein Structure, Secondary; Protein Structure, Tertiary; Quinoline; Quinolines - administration & dosage; Quinolines - chemistry; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Quinoline; Crystallography; PDE4; COPD
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.01.045

A series of quinoline-3-carboxamides has been identified as potent inhibitors of PDE4. The SAR has been explored and these studies have highlighted compounds
43 and
48 which show good potency, selectivity and rat PK suitable for oral dosing. The crystal structure of an example quinoline bound into the active site of PDE4 is also described.
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