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 (IC(50) = 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
P
Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, Maryland 21224, USA.
Jackson
Paul F
PF
Delahanty
Greg
G
Grella
Brian S
BS
Ko
Yao-Sen
YS
Li
Weixing
W
Liu
Qun
Q
Maclin
Keith M
KM
Poláková
Jana
J
Shaffer
Kathryn A
KA
Stoermer
Doris
D
Vitharana
Dilrukshi
D
Wang
Eric Yanjun
EY
Zakrzewski
Anthony
A
Rojas
Camilo
C
Slusher
Barbara S
BS
Wozniak
Krystyna M
KM
Burak
Eric
E
Limsakun
Tharin
T
Tsukamoto
Takashi
T
D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D003251:Constriction, Pathologic / Q000150:complications; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II; D005977:Glutarates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D008297:Male; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D010523:Peripheral Nervous System Diseases / Q000150:complications; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C474576:2-(3-mercaptopropyl)pentanedioic acid; D000700:Analgesics; D004791:Enzyme Inhibitors; D005977:Glutarates; D013438:Sulfhydryl Compounds; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II