2-MPPA - CAS 254737-29-6
Category: Inhibitor
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Molecular Formula:
C8H14O4S
Molecular Weight:
206.26
COA:
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Targets:
Carboxypeptidase
Description:
2-MPPA is a selective glutamate carboxypeptidase II (GCP II) inhibitor (IC50 = 90 nM), which is selective for GCP II over NMDA, kainate and AMPA glutamate receptors and MMP-1, -2, -3, -7, -9, ACE and NEP metalloproteases. 2-MPPA can be used in the treatment of neurological disorders associated with excessive activation of glutamatergic systems. Attenuates glutamate transmission resulting in the relief of neuropathic pain. This compound has neuroprotective properties.
Appearance:
White solid
Synonyms:
2-(3-Mercaptopropyl)pentanedioic acid
Solubility:
Water to 100 mM; DMSO to 100 mM
Storage:
Store in a cool and dry place (or refer to the Certificate of Analysis).
MSDS:
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InChIKey:
FNLNSQHJKVQCBP-UHFFFAOYSA-N
InChI:
InChI=1S/C8H14O4S/c9-7(10)4-3-6(8(11)12)2-1-5-13/h6,13H,1-5H2,(H,9,10)(H,11,12)
Canonical SMILES:
C(CC(CCC(=O)O)C(=O)O)CS
1.Structural optimization of thiol-based inhibitors of glutamate carboxypeptidase II by modification of the P1' side chain.
Majer P;Hin B;Stoermer D;Adams J;Xu W;Duvall BR;Delahanty G;Liu Q;Stathis MJ;Wozniak KM;Slusher BS;Tsukamoto T J Med Chem. 2006 May 18;49(10):2876-85.
A series of thiol-based inhibitors containing a benzyl moiety at the P1' position have been synthesized and tested for their abilities to inhibit glutamate carboxypeptidase II (GCP II). 3-(2-Carboxy-5-mercaptopentyl)benzoic acid 6c was found to be the most potent inhibitor with an IC(50) value of 15 nM, 6-fold more potent than 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), a previously discovered, orally active GCP II inhibitor. Subsequent SAR studies have revealed that the phenoxy and phenylsulfanyl analogues of 6c, 3-(1-carboxy-4-mercaptobutoxy)benzoic acid 26a and 3-[(1-carboxy-4-mercaptobutyl)thio]benzoic acid 26b, also possess potent inhibitory activities toward GCP II. In the rat chronic constriction injury (CCI) model of neuropathic pain, compounds 6c and 26a significantly reduced hyperalgesia following oral administration (1.0 mg/kg/day).
2.Pharmacokinetics and pharmacodynamics of the glutamate carboxypeptidase II inhibitor 2-MPPA show prolonged alleviation of neuropathic pain through an indirect mechanism.
Vornov JJ;Wozniak KM;Wu Y;Rojas C;Rais R;Slusher BS J Pharmacol Exp Ther. 2013 Sep;346(3):406-13. doi: 10.1124/jpet.113.205039. Epub 2013 Jun 17.
Glutamate carboxypeptidase II (GCP II) is a therapeutic target in neurologic disorders associated with excessive activation of glutamatergic systems. The potent, orally bioavailable GCP II inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) is effective in preclinical models of diseases where excess glutamate release is implicated, including neuropathic pain, and was the first GCP II inhibitor to be administered to man. The relationships between dosing regimen, pharmacokinetics, and analgesia in a neuropathic pain model were examined in rats to aid development of clinical dosing. The efficacy of oral 2-MPPA in the chronic constrictive injury model was not simply related to plasma concentrations. Even though maximal concentrations were observed within 1 hour of dosing, the analgesic effect took at least 8 days of daily dosing to become significant. The delay was not due to tissue drug accumulation since inhibitory concentrations of the drug were achieved in the nerve within 1 hour of dosing. There was also no accumulation of drug in plasma or tissue after multiple daily dosing. Effects were dependent on reaching a threshold concentration since dividing the daily dose led to a loss of effect.
3.δ-Thiolactones as prodrugs of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors.
Ferraris DV;Majer P;Ni C;Slusher CE;Rais R;Wu Y;Wozniak KM;Alt J;Rojas C;Slusher BS;Tsukamoto T J Med Chem. 2014 Jan 9;57(1):243-7. doi: 10.1021/jm401703a. Epub 2013 Dec 27.
δ-Thiolactones derived from thiol-based glutamate carboxypeptidase II (GCPII) inhibitors were evaluated as prodrugs. In rat liver microsomes, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA, 1) was gradually produced from 3-(2-oxotetrahydrothiopyran-3-yl)propionic acid (5), a thiolactone derived from 1. Compound 1 was detected in plasma at concentrations well above its IC50 for GCPII following oral administration of 5 in rats. Consistent with the oral plasma pharmacokinetics, thiolactone 5 exhibited efficacy in a rat model of neuropathic pain following oral administration.
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