Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors.
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.
Lunniss
C
C
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, England, UK. c.lunniss@biota.com.au
Eldred
C
C
Aston
N
N
Craven
A
A
Gohil
K
K
Judkins
B
B
Keeling
S
S
Ranshaw
L
L
Robinson
E
E
Shipley
T
T
Trivedi
N
N
D000284:Administration, Oral; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008252:Macaca fascicularis; D058988:Phosphodiesterase 4 Inhibitors; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
D006574:Heterocyclic Compounds, 2-Ring; D058988:Phosphodiesterase 4 Inhibitors; D011804:Quinolines; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C476282:cinnoline