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

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Abstract
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.