Chiral synthesis and pharmacological evaluation of NPS 1407: a potent, stereoselective NMDA receptor antagonist.
The stereoselective synthesis and biological activity of NPS 1407 (4a), (S)-(-)-3-amino-1,1-bis(3-fluorophenyl)butane, a potent, stereoselective antagonist of the NMDA receptor, are described. The racemate (4) was found to be active at the NMDA receptor in an in vitro assay, prompting the synthesis of the individual stereoisomers. The S isomer (4a) was found to be 12 times more potent than the R isomer (4b). Compound 4a demonstrated in vivo pharmacological activity in neuroprotection and anticonvulsant assays.
Moe
S T
ST
Medicinal Chemistry Pharmacology Groups, NPS Pharmaceuticals, Inc., Salt Lake City, UT 84108, USA. scotttmoe@yahoo.com
Smith
D L
DL
DelMar
E G
EG
Shimizu
S M
SM
Van Wagenen
B C
BC
Balandrin
M F
MF
Chien
Y E
YE
Raszkiewicz
J L
JL
Artman
L D
LD
White
H S
HS
Mueller
A L
AL
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy; D013237:Stereoisomerism
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate