Further studies—cimetidine analogues

Further studies on hydrophobicity were carried out by adding hydrophobic substituents to the isocytosine analogue (Fig. 13.45). These studies showed that there was an optimum hydrophobicity for activity corresponding to the equivalent of a butyl or pentyl substituent. A benzyl substituent was particularly good for activity, but proved to have toxic side-effects. These side-effects could be reduced by adding alkoxy substituents to the aromatic ring and this led to the synthesis of oxmetidine (Fig. 13.48) which had enhanced activity over cimetidine. Oxmetidine was considered for clinical use, but was eventually withdrawn since it still retained undesirable side-effects. 

Further studies on cimetidine analogues showed that the imidazole ring could be replaced with other nitrogen-containing heterocyclic rings. 

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