URMC-099
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MedKoo CAT#: 510349

CAS#: 1229582-33-5

Description: URMC-099 is an orally bioavailable, brain penetrant mixed lineage kinase (MLK) inhibitor with IC50 of 19 nM, 42 nM, 14 nM, and 150 nM, for MLK1, MLK2, MLK3, and DLK, respectively. MLK3 activation is associated with many of the pathologic hallmarks of HAND and therefore represents a prime target for adjunctive therapy based on small-molecule kinase inhibition. In vitro, URMC-099 treatment reduced inflammatory cytokine production by HIV-1 Tat-exposed microglia and prevented destruction and phagocytosis of cultured neuronal axons by these cells.


Chemical Structure

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URMC-099
CAS# 1229582-33-5

Theoretical Analysis

MedKoo Cat#: 510349
Name: URMC-099
CAS#: 1229582-33-5
Chemical Formula: C27H27N5
Exact Mass: 421.23
Molecular Weight: 421.550
Elemental Analysis: C, 76.93; H, 6.46; N, 16.61

Price and Availability

Size Price Availability Quantity
10mg USD 90 Ready to ship
25mg USD 150 Ready to ship
50mg USD 250 Ready to ship
100mg USD 450 Ready to ship
200mg USD 750 Ready to ship
500mg USD 1650 Ready to ship
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Synonym: URMC099, URMC 099, URMC-099

IUPAC/Chemical Name: 3-(1H-indol-5-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine

InChi Key: QKKIWEILHCXECO-UHFFFAOYSA-N

InChi Code: InChI=1S/C27H27N5/c1-31-10-12-32(13-11-31)18-19-2-4-20(5-3-19)23-15-24-25(17-30-27(24)29-16-23)21-6-7-26-22(14-21)8-9-28-26/h2-9,14-17,28H,10-13,18H2,1H3,(H,29,30)

SMILES Code: CN1CCN(CC2=CC=C(C3=CN=C(NC=C4C5=CC6=C(NC=C6)C=C5)C4=C3)C=C2)CC1

Appearance: White to off-white 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: URMC-099 is an orally bioavailable and potent mixed lineage kinase type 3 (MLK3) (IC50=14 nM) inhibitor with excellent blood-brain barrier penetration properties.
In vitro activity: URMC-099 (300 nM) blocked increases in JUN ( expression as well as phosphorylation at serine residues 63 and 73 (Fig. 3C,D; n = 3 cultures per condition, p = 0.015 for P Ser 73 JUN in 099- vs vehicle-treated cultures at 8 h and p = 0.003 at 12 h, one-way ANOVA with Sidak post hoc testw,x), consistent with reduced JNK (c-Jun N-terminal kinase) activity downstream of MLK inhibition. Treatment with CLFB1134 (a highly-specific MLK3 inhibitor with a different chemical scaffold) failed to provide protection or trophic support to NGF (nerve growth factor)-deprived neurons, which underwent neuritic beading and degeneration of cell bodies to an extent that precluded quantification of pyknotic versus healthy nuclei, suggesting that the neuroprotective effects of broad-spectrum MLK inhibition in vitro, like in vivo, are not reproduced by an inhibitor that is highly selective for MLK3. Thus, subsequent experiments focused on further characterizing the effects of URMC-099 in EAE (autoimmune encephalomyelitis) hippocampus. Reference: eNeuro. 2018 Nov-Dec; 5(6): ENEURO.0245-18.2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325567/
In vivo activity: At 24 h post-surgery, hippocampal microgliosis was observed in vehicle-treated mice receiving orthopedic surgery relative to sham-treated controls using stereological analyses of F4/80+ cells (P = 0.0003; Fig. 1a, b). In contrast, URMC-099-treated mice exhibited a significant reduction (P = 0.0003) in the density of F4/80+ cells in the hippocampus relative to the sham-treated controls (Fig. 1b), indicating that our treatment paradigm effectively inhibited surgery-induced hippocampal microgliosis. BBB integrity was examined also using IgG immunostaining. There was significantly less IgG leakage in URMC-099-treated mice receiving surgery and sham-treated controls when compared to vehicle-treated mice receiving surgery (P values ≤ 0.044; Fig. 1c). Hence, URMC-099 was efficacious in preventing both microgliosis and leakage at the BBB. Reference: J Neuroinflammation. 2019; 16: 193. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816182/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 29.0 68.79
DMF 25.0 59.30
DMF:PBS (pH 7.2) (1:1) 0.5 1.19
Ethanol 1.0 2.37

Preparing Stock Solutions

The following data is based on the product molecular weight 421.55 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. Bellizzi MJ, Hammond JW, Li H, Gantz Marker MA, Marker DF, Freeman RS, Gelbard HA. The Mixed-Lineage Kinase Inhibitor URMC-099 Protects Hippocampal Synapses in Experimental Autoimmune Encephalomyelitis. eNeuro. 2018 Dec 3;5(6):ENEURO.0245-18.2018. doi: 10.1523/ENEURO.0245-18.2018. PMID: 30627663; PMCID: PMC6325567. 2. Saminathan P, Kevadiya BD, Marker DF, Gendelman HE, Gorantla S, Gelbard HA. Broad Spectrum Mixed Lineage Kinase Type 3 Inhibition and HIV-1 Persistence in Macrophages. J Neuroimmune Pharmacol. 2019 Mar;14(1):44-51. doi: 10.1007/s11481-018-09829-8. Epub 2019 Jan 7. PMID: 30617749; PMCID: PMC6391203. 3. Miller-Rhodes P, Kong C, Baht GS, Saminathan P, Rodriguiz RM, Wetsel WC, Gelbard HA, Terrando N. The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders. J Neuroinflammation. 2019 Oct 28;16(1):193. doi: 10.1186/s12974-019-1582-5. PMID: 31660984; PMCID: PMC6816182. 4. Calamaras TD, Baumgartner RA, Aronovitz MJ, McLaughlin AL, Tam K, Richards DA, Cooper CW, Li N, Baur WE, Qiao X, Wang GR, Davis RJ, Kapur NK, Karas RH, Blanton RM. Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload. Am J Physiol Heart Circ Physiol. 2019 Jan 1;316(1):H145-H159. doi: 10.1152/ajpheart.00029.2018. Epub 2018 Oct 26. PMID: 30362822; PMCID: PMC6383356.
In vitro protocol: 1. Bellizzi MJ, Hammond JW, Li H, Gantz Marker MA, Marker DF, Freeman RS, Gelbard HA. The Mixed-Lineage Kinase Inhibitor URMC-099 Protects Hippocampal Synapses in Experimental Autoimmune Encephalomyelitis. eNeuro. 2018 Dec 3;5(6):ENEURO.0245-18.2018. doi: 10.1523/ENEURO.0245-18.2018. PMID: 30627663; PMCID: PMC6325567. 2. Saminathan P, Kevadiya BD, Marker DF, Gendelman HE, Gorantla S, Gelbard HA. Broad Spectrum Mixed Lineage Kinase Type 3 Inhibition and HIV-1 Persistence in Macrophages. J Neuroimmune Pharmacol. 2019 Mar;14(1):44-51. doi: 10.1007/s11481-018-09829-8. Epub 2019 Jan 7. PMID: 30617749; PMCID: PMC6391203.
In vivo protocol: 1. Miller-Rhodes P, Kong C, Baht GS, Saminathan P, Rodriguiz RM, Wetsel WC, Gelbard HA, Terrando N. The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders. J Neuroinflammation. 2019 Oct 28;16(1):193. doi: 10.1186/s12974-019-1582-5. PMID: 31660984; PMCID: PMC6816182. 2. Calamaras TD, Baumgartner RA, Aronovitz MJ, McLaughlin AL, Tam K, Richards DA, Cooper CW, Li N, Baur WE, Qiao X, Wang GR, Davis RJ, Kapur NK, Karas RH, Blanton RM. Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload. Am J Physiol Heart Circ Physiol. 2019 Jan 1;316(1):H145-H159. doi: 10.1152/ajpheart.00029.2018. Epub 2018 Oct 26. PMID: 30362822; PMCID: PMC6383356.

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1: Polesskaya O, Wong C, Lebron L, Chamberlain JM, Gelbard HA, Goodfellow V, Kim M, Daiss JL, Dewhurst S. MLK3 regulates fMLP-stimulated neutrophil motility. Mol Immunol. 2014 Apr;58(2):214-22. doi: 10.1016/j.molimm.2013.11.016. Epub 2014 Jan 3. PubMed PMID: 24389043; PubMed Central PMCID: PMC3946811.

2: Goodfellow VS, Loweth CJ, Ravula SB, Wiemann T, Nguyen T, Xu Y, Todd DE, Sheppard D, Pollack S, Polesskaya O, Marker DF, Dewhurst S, Gelbard HA. Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem. 2013 Oct 24;56(20):8032-48. doi: 10.1021/jm401094t. Epub 2013 Oct 3. PubMed PMID: 24044867; PubMed Central PMCID: PMC4032177.

3: Marker DF, Tremblay MÈ, Puccini JM, Barbieri J, Gantz Marker MA, Loweth CJ, Muly EC, Lu SM, Goodfellow VS, Dewhurst S, Gelbard HA. The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated neurocognitive disorders. J Neurosci. 2013 Jun 12;33(24):9998-10010. doi: 10.1523/JNEUROSCI.0598-13.2013. PubMed PMID: 23761895; PubMed Central PMCID: PMC3682381.