A series of novel quinoxaline heterocycle containing angiotensin II receptor antagonist analogs were prepared. This heterocycle was coupled to the biphenyl moiety via an oxygen atom linker instead of a carbon atom. Many of these analogs exhibit very potent activity and long duration of effect. Interestingly, the N-oxide quinoxaline analog was more potent than the nonoxidized quinoxaline as in the comparison of compounds 5 vs 30. In order to improve oral activity, the carboxylic acid function of these compounds was converted to the double ester. This change did result in an improvement in oral activity as represented by compound 44.
A series of bifunctional compounds with galactosyl residues as targeting ligand for asialoglycoprotein receptors on hepatocytes and various dendrimers as the DNA-binding domain was synthesized. When mixed with plasmid DNA, these compounds self assembled into particles that exhibited high transfection activity both in vitro and in vivo. Optimal activity in liver cells was observed with compounds containing three galactosyl residues and 16 dendrimer arms. These results suggest that domain-based design is an effective strategy for development of a new generation of synthetic gene carriers.
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