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

Article abstract of DOI:10.1016/j.bmcl.2009.11.010

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.