8-Substituted Xanthines as Phosphodiesterase Inhibitors: Conformation-Dependent Lipophilicity and Structure-Activity Relationships

The 8-substituted xanthines 1 – 21 (including compound S 9795), caffeine ( 22 ), and the three isomeric dimethyl-xanthines 23 – 25 (see Table 1), were examined for their lipophilic behaviour using a reversed-phase HPLC technique. A number of flexible compounds showed a smaller-than-expected lipophilicity which based on conformational and tautomeric calculations were ascribed to the predominance of folded forms. A QSAR analysis of the phosphodiesterase-inhibitory potency of several compounds showed favourable factors to be a low lipophilicity and the absence of a substituent on the N⁷ position.