Novel selective PDE IV inhibitors as antiasthmatic agents. Synthesis and biological activities of a series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans.

A series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans have been synthesized and evaluated for their ability to selectively inhibit PDE IV isolated from guinea pig. Replacement of the 1-phenyl ring by a pyridone ring led to marked improvement of their selectivity for PDE IV over PDE III. The compounds that were most potent and selective involved those bearing an N-alkylpyridone ring at C-1. These compounds also showed potent antispasmogenic activity without causing significant changes in heart rate in the guinea pig. The most potent compound was 6,7-diethoxy-2, 3-bis(hydroxymethyl)-1-[1-(2-methoxyethyl)-2-oxo-pyrid-4-yl]nap hth alene (17f), ED50 values of histamine-induced and antigen-induced bronchoconstriction in the guinea pig being 0.08 and 2.3 mg/kg iv, respectively. This compound was chosen as a candidate for further pharmacological evaluation.