2-PMPA - CAS 173039-10-6
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
2-PMPA is highly potent and selective inhibitor of glutamate carboxypeptidase 2 (Ki= 275 pM) and the neuropeptidase N-acetylated α-linked acidic dipeptidase (NAALADase).
Brife Description:
A highly potent and selective inhibitor of glutamate carboxypeptidase 2 (Ki= 275 pM)
2-(phosphonomethyl)pentanedioic acid; 2-PMPA cpd
H2O: ≥ 28 mg/mL
Store in a cool and dry place (or refer to the Certificate of Analysis).
Boiling Point:
538.8±60.0 ℃ at 760 Torr
1.658±0.06 g/cm3
Canonical SMILES:
1.Bioanalytical method for evaluating the pharmacokinetics of the GCP-II inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA).
Rais R1, Rojas C, Wozniak K, Wu Y, Zhao M, Tsukamoto T, Rudek MA, Slusher BS. J Pharm Biomed Anal. 2014 Jan;88:162-9. doi: 10.1016/j.jpba.2013.08.028. Epub 2013 Aug 30.
2-Phosphonomethyl pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II, an enzyme which catabolizes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to N-acetylaspartate (NAA) and glutamate. 2-PMPA demonstrates robust efficacy in numerous animal models of neurological disease, however its pharmacokinetics has not yet been fully described. 2-PMPA is a highly polar compound with multiple negative charges causing significant challenges for analysis in biological matrices. Here we report a derivatization method for the acidic groups that involved protein precipitation with acetonitrile followed by reaction with N-tert-butyldimethysilyl-N-methyltrifluoroacetamide (MTBSTFA). The silylated analyte with transitions (683→551.4) and the internal standard (669→537.2) were monitored by tandem mass spectrometry with electrospray positive ionization mode. The method was subsequently used to evaluate 2-PMPA pharmacokinetics in rats.
2.Preparation of asymmetric urea derivatives that target prostate-specific membrane antigen for SPECT imaging.
Harada N1, Kimura H, Ono M, Saji H. J Med Chem. 2013 Oct 24;56(20):7890-901. doi: 10.1021/jm400895s. Epub 2013 Oct 9.
Prostate-specific membrane antigen (PSMA) has been identified as a diagnostic and therapeutic target for prostate cancer. (S)-2-[3-[(R)-1-Carboxy-2-mercaptoethyl]ureido-pentanedioic acid (Cys-CO-Glu) were used to design novel PSMA targeting probes by nucleophilic conjugate addition between cysteine and maleimide based reagents. 3 ([(123)I]IGLCE) was synthesized by this strategy and showed high affinity for PSMA. Results of binding inhibition assays of these derivatives suggested the importance of an aromatic group and succinimide moiety for high affinity. [(123)I]3 was evaluated in vivo with PSMA positive LNCaP and PSMA negative PC-3 human prostate cancer xenograft bearing mice. [(125)I]3 accumulated in LNCaP tumors but not in PC-3 tumors, and the accumulation was inhibited by 2-(phosphonomethyl)pentanedioic acid (2-PMPA). Use of [(123)I]3 provided positive images of LNCaP tumors in single photon emission tomography scans. These results warrant further evaluation of [(123)I]3 and its derivatives as radiolabeled probes for the diagnosis of prostate cancer.
3.Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration.
Rais R1, Wozniak K2, Wu Y2, Niwa M3, Stathis M2, Alt J2, Giroux M4, Sawa A3, Rojas C5, Slusher BS6. PLoS One. 2015 Jul 7;10(7):e0131861. doi: 10.1371/journal.pone.0131861. eCollection 2015.
Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n.) administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based), 2-MPPA (thiol-based) and 2-PMPA (phosphonate-based). While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation.
4.Preparation and evaluation of carborane-derived inhibitors of prostate specific membrane antigen (PSMA).
El-Zaria ME1, Genady AR, Janzen N, Petlura CI, Beckford Vera DR, Valliant JF. Dalton Trans. 2014 Apr 7;43(13):4950-61. doi: 10.1039/c3dt53189a.
A series of C-hydroxy carborane derivatives of (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)-pentanedioic acid were prepared as a new class of boron rich inhibitors of prostate specific membrane antigen (PSMA), which is overexpressed on prostate cancer tumours and metastases. Closo-, nido- and iodo-carborane conjugates were prepared and screened in vitro where the water soluble iodinated cluster had the highest affinity with an IC50 value (73.2 nM) that was comparable to a known PSMA inhibitor 2-(phosphonomethyl)-pentanedioic acid (PMPA, 63.9 nM). The radiolabeled analogue was prepared using (123)I and the biodistribution determined in a prostate cancer model derived from a PSMA positive cell line (LNCaP) at 1, 2, 4, 6 and 24 h post injection (n = 4 per time point). The results showed good initial tumour uptake of 4.17% at 1 h, which remained at that level only decreasing somewhat at 6 h (3.59%). At the latter time point tumour-to-blood and tumour-to-muscle ratios peaked at 3.
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