Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors

C Lunniss; C Eldred; N Aston; A Craven; K Gohil; B Judkins; S Keeling; L Ranshaw; E Robinson; T Shipley; N Trivedi

doi:10.1016/j.bmcl.2009.11.010

Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors

Bioorg Med Chem Lett. 2010 Jan 1;20(1):137-40. doi: 10.1016/j.bmcl.2009.11.010. Epub 2009 Nov 10.

Authors

C Lunniss¹, C Eldred, N Aston, A Craven, K Gohil, B Judkins, S Keeling, L Ranshaw, E Robinson, T Shipley, N Trivedi

Affiliation

¹ GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, England, UK. c.lunniss@biota.com.au

PMID: 19932963
DOI: 10.1016/j.bmcl.2009.11.010

Abstract

Species specific conversion of the lead PDE4 inhibitor 1 to the quinolone 3 was identified as the major route of metabolism in the cynomolgus monkey. Modification of the template to give the cinnoline 9 retained potency and selectivity, and greatly improved the pharmacokinetic profile in the cynomolgus monkey compared with 1. Additional SAR studies aimed at improving the solubility of 9 are also described.

MeSH terms

Administration, Oral
Animals
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
Heterocyclic Compounds, 2-Ring / chemical synthesis
Heterocyclic Compounds, 2-Ring / chemistry*
Heterocyclic Compounds, 2-Ring / pharmacokinetics
Macaca fascicularis
Phosphodiesterase 4 Inhibitors*
Quinolines / chemical synthesis
Quinolines / chemistry*
Quinolines / pharmacokinetics
Rats
Solubility
Structure-Activity Relationship

Substances

Heterocyclic Compounds, 2-Ring
Phosphodiesterase 4 Inhibitors
Quinolines
Cyclic Nucleotide Phosphodiesterases, Type 4
cinnoline