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

…, B Judkins, S Keeling, L Ranshaw, E Robinson…

Index: Lunniss; Eldred; Aston; Craven; Gohil; Judkins; Keeling; Ranshaw; Robinson; Shipley; Trivedi Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 1 p. 137 - 140

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Citation Number: 15

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.