Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II: Discovery of an orally active GCP II inhibitor
A series of 2-(thioalkyl)pentanedioic acids were synthesized and evaluated as inhibitors of glutamate carboxypeptidase II (GCP II, EC 3.4.17.21). The inhibitory potency of these thiol-based compounds against GCP II was found to be dependent on the number of methylene units between the thiol group and pentanedioic acid. A comparison of the SAR of the thiol-based inhibitors to that of the phosphonate-based inhibitors provides insight into the role of each of the two zinc-binding groups in GCP II inhibition. The most potent thiol-based inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (IC50 = 90 nM), was found to be orally bioavailable in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.
Majer, Pavel,Jackson, Paul F.,Delahanty, Greg,Grella, Brian S.,Ko, Yao-Sen,Li, Weixing,Liu, Qun,Maclin, Keith M.,Poláková, Jana,Shaffer, Kathryn A.,Stoermer, Doris,Vitharana, Dilrukshi,Yanjun Wang, Eric,Zakrzewski, Anthony,Rojas, Camilo,Slusher, Barbara S.,Wozniak, Krystyna M.,Burak, Eric,Limsakun, Tharin,Tsukamoto, Takashi
p. 1989 - 1996
(2007/10/03)
NAALADase inhibitors useful as pharmaceutical compounds and compositions
The present invention relates to N-Acetylated α-Linked Acidic Dipeptidase (NAALADase) inhibitors enzyme activity, pharmaceutical compositions comprising such inhibitors, and methods of their use to inhibit NAALADase enzyme activity, thereby effecting neur
-
(2008/06/13)
Methods for treating anxiety, anxiety disorders and memory impairment using naaladase inhibitors
The present invention relates to methods of using NAALADase inhibitors for treating glutamate-mediated diseases, disorders and conditions selected from the group consisting of anxiety, anxiety disorders and memory impairment.
-
(2008/06/13)
More Articles about upstream products of 254737-42-3