A unified approach to systematic isosteric substitution for acidic groups and application to NMDA antagonists related to 2-amino-7-phosphonoheptanoate.
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.
Chenard
B L
BL
Central Research, Pfizer Inc., Groton, Connecticut 06340.
Lipinski
C A
CA
Dominy
B W
BW
Mena
E E
EE
Ronau
R T
RT
Butterfield
G C
GC
Marinovic
L C
LC
Pagnozzi
M
M
Butler
T W
TW
Tsang
T
T
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D016202:N-Methylaspartate; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D013329:Structure-Activity Relationship
D000596:Amino Acids; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; C031231:2-amino-7-phosphonoheptanoic acid