A Unified Approach to Systematic Isoesteric Substitution for Acidic Groups and Application to NMDA Antagonists Related to 2-Amino-7-phosphonoheptanoate

Article abstract of DOI:10.1021/jm00165a030

A systematic approach to the replacement of acidic groups with potential bioisoesteres 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 pK_a 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 isoesteres 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.