NBI-74330
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MedKoo CAT#: 206469

CAS#: 855527-92-3 (R-isomer)

Description: NBI-74330 is an antagonist of CXC chemokine receptor 3 (CXCR3) with IC50 values of 7nM to18nM. NBI-74330 attenuates atherosclerotic plaque formation in LDL receptor-deficient mice. Chemokine receptor CXCR3 promotes growth of glioma. CXCR3 antagonism exerts a direct anti-glioma effect and this receptor may be a potential therapeutic target for treating human GBM.


Chemical Structure

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NBI-74330
CAS# 855527-92-3 (R-isomer)

Theoretical Analysis

MedKoo Cat#: 206469
Name: NBI-74330
CAS#: 855527-92-3 (R-isomer)
Chemical Formula: C32H27F4N5O3
Exact Mass: 605.21
Molecular Weight: 605.590
Elemental Analysis: C, 63.47; H, 4.49; F, 12.55; N, 11.56; O, 7.93

Price and Availability

Size Price Availability Quantity
5mg USD 150 Ready to ship
10mg USD 250 Ready to ship
25mg USD 450 Ready to ship
50mg USD 850 Ready to ship
100mg USD 1350 Ready to ship
200mg USD 1950 Ready to ship
500mg USD 2650 Ready to ship
1g USD 3450 Ready to ship
2g USD 6450 Ready to ship
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Related CAS #: 473722-68-8 (racemate)   855527-92-3 (R-isomer)    

Synonym: NBI-74330; NBI 74330; NBI74330.

IUPAC/Chemical Name: N-[(1R)-1-[3-(4-Ethoxyphenyl)-3,4-dihydro-4-oxopyrido[2,3-d]pyrimidin-2-yl]ethyl]-4-fluoro-N-(3-pyridinylmethyl)-3-(trifluoromethyl)benzeneacetamide

InChi Key: XMRGQUDUVGRCBS-HXUWFJFHSA-N

InChi Code: InChI=1S/C32H27F4N5O3/c1-3-44-24-11-9-23(10-12-24)41-30(39-29-25(31(41)43)7-5-15-38-29)20(2)40(19-22-6-4-14-37-18-22)28(42)17-21-8-13-27(33)26(16-21)32(34,35)36/h4-16,18,20H,3,17,19H2,1-2H3/t20-/m1/s1

SMILES Code: O=C(N([C@@H](C1=NC2=NC=CC=C2C(N1C3=CC=C(OCC)C=C3)=O)C)CC4=CC=CN=C4)CC5=CC=C(F)C(C(F)(F)F)=C5

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Biological target: NBI-74330 is a potent antagonist for CXCR3, and exhibits potent inhibition of (125I)CXCL10 and (125I)CXCL11 specific binding with Ki of 1.5 and 3.2 nM, respectively.
In vitro activity: It has been suggested that CXCR3 is important for nociception. Experiments were conducted to evaluate involvement of CXCR3 and its ligands (CXCL4, CXCL9, CXCL10, CXCL11/CCL21) in neuropathic pain. Spinal glial cells, particularly microglial, are highly activated in neuropathic pain. Additionally, the activation of these cells induces the release of a broad spectrum of nociceptive mediators including chemokines.Overall, upon these data we cannot explicitly state that CXCR3 does co-localize with microglia, however based on our in vitro study it is tempting to hypothesize that the direct influence of (±)-NBI-74330 on spinal microglia is possible, since it possesses the ability to reduce the level of CXCL10 in LPS activated microglia (Supplementary SFig. 3). In vitro studies provided evidence that (±)-NBI-74330 potently inhibits the binding of CXCL10/CXCL11 to CXCR3 in basophilic leukaemia cells , diminished CXCL11-induced chemotaxis in human T cells and block the CXCR3 internalization in murine DO11.10 cells stimulated with CXCL9, CXCL10 or CXCL11. Therefore ((±)-NBI-74330) is able to diminish the LPS-induced upregulation of CXCL10 and CXCL11 in both glial cell cultures. It is hypothesized that CXCR3 located on neuronal and – if confirmed – on part of microglial cell population, might play an important role in neuron-glial cross-talk under neuropathic pain, however this issue is just opening and interesting perspective to further studies in the future. Biochim Biophys Acta Mol Basis Dis. 2018 Oct;1864(10):3418-3437. doi: 10.1016/j.bbadis.2018.07.032. Epub 2018 Aug 1. https://pubmed.ncbi.nlm.nih.gov/30076959/
In vivo activity: To test whether human CXCR3 inhibitors interfere with Cxcr3.2 function in medaka and block osteoclast formation, we treated ctsk:GFP/mpeg1:mCherry/rankl:HSE:cfp transgenic medaka with different doses of NBI-74330 and AMG487, two structurally related antagonists of human CXCR3, with slightly different binding affinities. The inhibitor NBI-74330 was dissolved in DMSO and 100% ethanol to make 30 mM stocks. For NBI-74330, larvae were kept in fish medium containing 30 μM NBI-74330 for 3 h prior to heat shock, changed to the pure fish medium during heat shock, and then reverted to drug solution for the course of the experiment. In NBI-74330–treated larvae at 1 dphs, the number of initially recruited macrophages was not significantly different from controls (Fig. 4 A and B); however, fewer macrophages were detectable in the region of the vertebral arches (Fig. 4E, white arrows). In contrast, at 2 dphs, when macrophage numbers increased strongly in controls, they remained at significantly lower levels in NBI-74330–treated larvae (Fig. 4B). Importantly, the total number of macrophages, including those in the AGM and tail region, was not significantly altered (Fig. 4C). Also osteoclast formation was strongly suppressed in NBI-74330–treated larvae (Fig. 4 A, D, and E). As a consequence, treatment with NBI-74330 protected bone integrity upon Rankl induction (Fig. 4E). NBI-74330–treated larvae showed a significant reduction of mineralization defects and were almost indistinguishable from Rankl-negative larvae (Fig. 4E). Furthermore, Cxcr3.2 inhibition by the chemical antagonists AMG487 and NBI-74330 also reduced osteoclast recruitment and protected bone integrity against osteoporotic insult. Our data identify a mechanism for progenitor recruitment to bone resorption sites and Cxcl9l and Cxcr3.2 as potential druggable regulators of bone homeostasis and osteoporosis. Proc Natl Acad Sci U S A. 2020 Aug 11; 117(32): 19276–19286. Published online 2020 Jul 27. doi: 10.1073/pnas.2006093117 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431079/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 165.10

Preparing Stock Solutions

The following data is based on the product molecular weight 605.59 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Piotrowska A, Rojewska E, Pawlik K, Kreiner G, Ciechanowska A, Makuch W, Zychowska M, Mika J. Pharmacological blockade of CXCR3 by (±)-NBI-74330 reduces neuropathic pain and enhances opioid effectiveness - Evidence from in vivo and in vitro studies. Biochim Biophys Acta Mol Basis Dis. 2018 Oct;1864(10):3418-3437. doi: 10.1016/j.bbadis.2018.07.032. Epub 2018 Aug 1. PMID: 30076959. 2. Liu C, Luo D, Reynolds BA, Meher G, Katritzky AR, Lu B, Gerard CJ, Bhadha CP, Harrison JK. Chemokine receptor CXCR3 promotes growth of glioma. Carcinogenesis. 2011 Feb;32(2):129-37. doi: 10.1093/carcin/bgq224. Epub 2010 Nov 3. PMID: 21051441; PMCID: PMC3026840. 3. Phan QT, Tan WH, Liu R, Sundaram S, Buettner A, Kneitz S, Cheong B, Vyas H, Mathavan S, Schartl M, Winkler C. Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model. Proc Natl Acad Sci U S A. 2020 Aug 11;117(32):19276-19286. doi: 10.1073/pnas.2006093117. Epub 2020 Jul 27. PMID: 32719141; PMCID: PMC7431079. 4. Jopling LA, Watt GF, Fisher S, Birch H, Coggon S, Christie MI. Analysis of the pharmacokinetic/pharmacodynamic relationship of a small molecule CXCR3 antagonist, NBI-74330, using a murine CXCR3 internalization assay. Br J Pharmacol. 2007 Dec;152(8):1260-71. doi: 10.1038/sj.bjp.0707519. Epub 2007 Nov 5. PMID: 17982480; PMCID: PMC2190000.
In vitro protocol: 1. Piotrowska A, Rojewska E, Pawlik K, Kreiner G, Ciechanowska A, Makuch W, Zychowska M, Mika J. Pharmacological blockade of CXCR3 by (±)-NBI-74330 reduces neuropathic pain and enhances opioid effectiveness - Evidence from in vivo and in vitro studies. Biochim Biophys Acta Mol Basis Dis. 2018 Oct;1864(10):3418-3437. doi: 10.1016/j.bbadis.2018.07.032. Epub 2018 Aug 1. PMID: 30076959. 2. Liu C, Luo D, Reynolds BA, Meher G, Katritzky AR, Lu B, Gerard CJ, Bhadha CP, Harrison JK. Chemokine receptor CXCR3 promotes growth of glioma. Carcinogenesis. 2011 Feb;32(2):129-37. doi: 10.1093/carcin/bgq224. Epub 2010 Nov 3. PMID: 21051441; PMCID: PMC3026840.
In vivo protocol: 1. Phan QT, Tan WH, Liu R, Sundaram S, Buettner A, Kneitz S, Cheong B, Vyas H, Mathavan S, Schartl M, Winkler C. Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model. Proc Natl Acad Sci U S A. 2020 Aug 11;117(32):19276-19286. doi: 10.1073/pnas.2006093117. Epub 2020 Jul 27. PMID: 32719141; PMCID: PMC7431079. 2. Jopling LA, Watt GF, Fisher S, Birch H, Coggon S, Christie MI. Analysis of the pharmacokinetic/pharmacodynamic relationship of a small molecule CXCR3 antagonist, NBI-74330, using a murine CXCR3 internalization assay. Br J Pharmacol. 2007 Dec;152(8):1260-71. doi: 10.1038/sj.bjp.0707519. Epub 2007 Nov 5. PMID: 17982480; PMCID: PMC2190000.

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1: Scholten DJ, Roumen L, Wijtmans M, Verkade-Vreeker MC, Custers H, Lai M, de Hooge D, Canals M, de Esch IJ, Smit MJ, de Graaf C, Leurs R. Identification of overlapping but differential binding sites for the high-affinity CXCR3 antagonists NBI-74330 and VUF11211. Mol Pharmacol. 2014 Jan;85(1):116-26. doi: 10.1124/mol.113.088633. Epub 2013 Oct 30. PubMed PMID: 24174496.

2: Watts AO, Scholten DJ, Heitman LH, Vischer HF, Leurs R. Label-free impedance responses of endogenous and synthetic chemokine receptor CXCR3 agonists correlate with Gi-protein pathway activation. Biochem Biophys Res Commun. 2012 Mar 9;419(2):412-8. doi: 10.1016/j.bbrc.2012.02.036. Epub 2012 Feb 13. PubMed PMID: 22349504.

3: Korniejewska A, McKnight AJ, Johnson Z, Watson ML, Ward SG. Expression and agonist responsiveness of CXCR3 variants in human T lymphocytes. Immunology. 2011 Apr;132(4):503-15. doi: 10.1111/j.1365-2567.2010.03384.x. Epub 2011 Jan 24. PubMed PMID: 21255008; PubMed Central PMCID: PMC3075504.

4: Liu C, Luo D, Reynolds BA, Meher G, Katritzky AR, Lu B, Gerard CJ, Bhadha CP, Harrison JK. Chemokine receptor CXCR3 promotes growth of glioma. Carcinogenesis. 2011 Feb;32(2):129-37. doi: 10.1093/carcin/bgq224. Epub 2010 Nov 3. PubMed PMID: 21051441; PubMed Central PMCID: PMC3026840.

5: Kapoor S. Emerging new chemokine CXCR3 antagonists and their potential clinical and therapeutic applications. Hepatology. 2009 Apr;49(4):1400-1. doi: 10.1002/hep.22781. PubMed PMID: 19330874.

6: Verzijl D, Storelli S, Scholten DJ, Bosch L, Reinhart TA, Streblow DN, Tensen CP, Fitzsimons CP, Zaman GJ, Pease JE, de Esch IJ, Smit MJ, Leurs R. Noncompetitive antagonism and inverse agonism as mechanism of action of nonpeptidergic antagonists at primate and rodent CXCR3 chemokine receptors. J Pharmacol Exp Ther. 2008 May;325(2):544-55. doi: 10.1124/jpet.107.134783. Epub 2008 Feb 12. PubMed PMID: 18270317; PubMed Central PMCID: PMC3659174.

7: van Wanrooij EJ, de Jager SC, van Es T, de Vos P, Birch HL, Owen DA, Watson RJ, Biessen EA, Chapman GA, van Berkel TJ, Kuiper J. CXCR3 antagonist NBI-74330 attenuates atherosclerotic plaque formation in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):251-7. Epub 2007 Nov 29. PubMed PMID: 18048768.

8: Jopling LA, Watt GF, Fisher S, Birch H, Coggon S, Christie MI. Analysis of the pharmacokinetic/pharmacodynamic relationship of a small molecule CXCR3 antagonist, NBI-74330, using a murine CXCR3 internalization assay. Br J Pharmacol. 2007 Dec;152(8):1260-71. Epub 2007 Nov 5. PubMed PMID: 17982480; PubMed Central PMCID: PMC2190000.

9: Storelli S, Verzijl D, Al-Badie J, Elders N, Bosch L, Timmerman H, Smit MJ, De Esch IJ, Leurs R. Synthesis and structure-activity relationships of 3H-quinazolin-4-ones and 3H-pyrido[2,3-d]pyrimidin-4-ones as CXCR3 receptor antagonists. Arch Pharm (Weinheim). 2007 Jun;340(6):281-91. PubMed PMID: 17562560.

10: Heise CE, Pahuja A, Hudson SC, Mistry MS, Putnam AL, Gross MM, Gottlieb PA, Wade WS, Kiankarimi M, Schwarz D, Crowe P, Zlotnik A, Alleva DG. Pharmacological characterization of CXC chemokine receptor 3 ligands and a small molecule antagonist. J Pharmacol Exp Ther. 2005 Jun;313(3):1263-71. Epub 2005 Mar 10. PubMed PMID: 15761110.