|
|||||
|
|
Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration |
|
| Authors: | Michael D. Woodrow Stuart P. Ballantine Michael D. Barker Beth J. Clarke John Dawson Tony W. Dean Christopher J. Delves Brian Evans Sharon L. Gough Steven B. Guntrip Stuart Holman Duncan S. Holmes Michael Kranz Mika K. Lindvaal Fiona S. Lucas Margarete Neu Lisa E. Ranshaw Yemisi E. Solanke Don O. Somers Peter Ward Joanne O. Wiseman |
| Affiliation: | 1. Immuno-Inflammation CEDD Medicinal Chemistry Dept, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK;2. Respiratory CEDD Medicinal Chemistry Dept, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK;3. Molecular Discovery Research Medicinal Chemistry Dept, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK;4. Respiratory Biology Dept, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK;5. DMPK Dept, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK;6. Computational and Structural Chemistry Dept, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK;7. Biological Reagents and Assay Development Dept, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK |
| Abstract: | Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-α from isolated human peripheral blood mononuclear cells with a pIC50 of 11.1. GSK256066 also has a suitable profile for inhaled dosing. |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ | |