title: Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors.
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.
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, England, UK. c.lunniss@biota.com.au
authors.forename: C
authors.initials: C
authors.lastname: Lunniss
authors.forename: C
authors.initials: C
authors.lastname: Eldred
authors.forename: N
authors.initials: N
authors.lastname: Aston
authors.forename: A
authors.initials: A
authors.lastname: Craven
authors.forename: K
authors.initials: K
authors.lastname: Gohil
authors.forename: B
authors.initials: B
authors.lastname: Judkins
authors.forename: S
authors.initials: S
authors.lastname: Keeling
authors.forename: L
authors.initials: L
authors.lastname: Ranshaw
authors.forename: E
authors.initials: E
authors.lastname: Robinson
authors.forename: T
authors.initials: T
authors.lastname: Shipley
authors.forename: N
authors.initials: N
authors.lastname: Trivedi
mesh_terms: 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
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; D058988:Phosphodiesterase 4 Inhibitors; D011804:Quinolines; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C476282:cinnoline