A unified approach to systematic isosteric substitution for acidic groups and application to NMDA antagonists related to 2-amino-7-phosphonoheptanoate

Abstract

A systematic approach to the replacement of acidic groups with potential bioisosteres is described. The strategy involves simple nucleophilic displacement of a common alkyl halide precursor with a variety of mercaptoazoles and related molecules. The mercaptoazoles and their oxidized derivatives (sulfinyl- and sulfonylazoles) represent a series of possible surrogates for acidic groups which span a pKa range from about 4.5-11.5. This simple strategy was extended to include 2-hydroxy- or 2-aminothiophenyl groups which function as relatively nonacidic isosteres for a phosphonic acid. By replacing the phosphonic acid of 2-amino-7-phosphonoheptanoate (AP-7) with these groups, we have synthesized novel N-methyl-d-aspartate (NMDA) antagonists.