Alkyl-bridged substituted 8-arylquinolines as highly potent PDE IV inhibitors

Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors based on the SAR described herein. Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.