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.
Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, Maryland 21224, USA.
Pavel
P
Majer
Paul F
PF
Jackson
Greg
G
Delahanty
Brian S
BS
Grella
Yao-Sen
YS
Ko
Weixing
W
Li
Qun
Q
Liu
Keith M
KM
Maclin
Jana
J
Poláková
Kathryn A
KA
Shaffer
Doris
D
Stoermer
Dilrukshi
D
Vitharana
Eric Yanjun
EY
Wang
Anthony
A
Zakrzewski
Camilo
C
Rojas
Barbara S
BS
Slusher
Krystyna M
KM
Wozniak
Eric
E
Burak
Tharin
T
Limsakun
Takashi
T
Tsukamoto
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