| Abstract: | The efficient synthesis of a family of twelve acidic heterocycles of varying acidity from a single common intermediate facilitates the search for new acidic bioisosteres. An extension of this chemical approach led to a new family of phosphonate replacements in prototypes related to the N-methyl Dasparate (NMDA) antagonist 2-amino-7-phosphonoheptanoic acid (AP7). Acidic isostere design may be facilitated by grouping hydroxylic heterocyclic carboxylic isosteres into one of two electronic classes based on the Gandour hypothesis. The limitations of normal hydroxamic acids as carboxylic acid surrogates suggest that the excellent metabolic stability of reverse hydroxamic acids may be useful in prospective acidic isostere design. |
