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| Targets |
NCX 470 is a prostaglandin analog that primarily targets the FP prostaglandin receptor. Additionally, through its NO-donating function, it releases nitric oxide, which acts as a signaling molecule to relax the trabecular meshwork. This dual mechanism simultaneously activates bimatoprost-mediated uveoscleral outflow and NO-mediated conventional outflow pathways.
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| ln Vitro |
In vitro studies demonstrate that NCX 470 is an agonist at prostaglandin receptors, primarily FP. The compound does not have inherent binding activity on its own, and its biological effects are mediated by its active metabolites. The NO component is also confirmed to be pharmacologically active in relaxing smooth muscle cells.
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| ln Vivo |
In well-researched animal models of glaucoma and ocular hypertension, bimatoprost grenod has superior intraocular pressure-lowering effectiveness than equimolar dosages of bimatoprost[1]. Bimatoprost grenod (0.14% 30 μL; once-dose instillation) lowers intraocular pressure in rabbits with transitory ocular hypertension[2]. At eighteen hours after dosage, bimatoprost grenod (0.042% 30 μL; instillation; once) is more efficacious than equimolar bimatoprost in normotensive dogs (ONT-dogs) and cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys)[2].
NCX 470 effectively reduces intraocular pressure in animal models of ocular hypertension and glaucoma. This is achieved by activating both the bimatoprost-mediated uveoscleral outflow and the NO-mediated conventional outflow pathways. The dual-action mechanism has been shown to provide enhanced IOP lowering compared to either pathway alone. |
| Enzyme Assay |
Specific protocols for assessing NO donation involve incubating NCX 470 with a reducing agent (e.g., L-cysteine) in a buffer. The liberated NO is then measured using a chemiluminescence NO analyzer or the Griess reagent system for nitrite quantification. For FP receptor binding, standard radioligand displacement assays are used. Membranes from cells expressing human recombinant FP receptors are incubated with [3H]-PGF2alpha and varying concentrations of NCX 470 or its active metabolites.
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| Cell Assay |
In an in vitro assay, primary human trabecular meshwork (HTM) cells are cultured in a suitable medium. Following serum starvation, the cells are treated with NCX 470 (ranging from 0.1 nM to 10 uM). The cellular effects are measured by quantifying intracellular cGMP levels (as a direct biomarker of NO activity) using an ELISA kit. Alternatively, receptor activation can be assessed by detecting the phosphorylation of downstream signaling proteins like ERK1/2 via Western blot.
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| Animal Protocol |
Animal/Disease Models: New Zealand white rabbits with 0.1 mL 5% sodium chloride solution injection[2]
Doses: 0.14% Route of Administration: Instillation; 0.14% 30 μL; once Experimental Results: Dramatically blunted the IOP rise throughout the experimental period in transiently ocular hypertensive New Zealand white rabbits. In a standard in vivo protocol, ocular hypertension is induced in New Zealand White rabbits via intracameral injection of alpha-chymotrypsin or laser photocoagulation of the trabecular meshwork. Once elevated IOP is stable, a single topical administration (approximately 30 microL) of NCX 470 is applied to the eye at varying concentrations (0.004% to 0.1%). IOP is measured using a calibrated tonometer at baseline and at multiple time points (e.g., 2, 4, 6, 8, 12, 24 hours) post-instillation. |
| ADME/Pharmacokinetics |
As a topical ocular agent, NCX 470 is designed for local delivery. Systemic absorption is expected to be minimal following eye drop instillation, which reduces the risk of systemic side effects. The compound acts as a prodrug, requiring activation by endogenous esterases in the eye to release the active bimatoprost and generate NO. The NO component has a very short local half-life.
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| Toxicity/Toxicokinetics |
As it is administered topically, systemic toxicity for NCX 470 is expected to be low. Local ocular toxicity assessments from analog studies may include mild conjunctival hyperemia, increase in iris pigmentation, and potential for eyelash growth (trichiasis). Systemic toxicity studies in animal models (rats and dogs) for similar compounds have shown a sufficient safety margin for ophthalmic indications, with no significant carcinogenicity or genotoxicity observed.
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| References |
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| Additional Infomation |
6-(nitrooxy)-hexanoic acid, (1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester is a small molecule drug. The monoisotopic molecular weight of bimatoprost glibenclamide is 574.33 Da.
NCX 470 has been granted Fast Track designation by the U.S. FDA. As of now, NCX 470 is in late-stage clinical development (Phase III clinical trials) for the reduction of intraocular pressure in patients with open-angle glaucoma and ocular hypertension. Its mechanism of action aims to provide superior IOP reduction by targeting both the conventional and uveoscleral outflow pathways. |
| Molecular Formula |
C31H46N2O8
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|---|---|
| Molecular Weight |
574.705549716949
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| Exact Mass |
574.325
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| CAS # |
1194396-71-8
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| PubChem CID |
44462739
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| Appearance |
Colorless to light yellow ointment
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| LogP |
4.7
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
20
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| Heavy Atom Count |
41
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| Complexity |
821
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| Defined Atom Stereocenter Count |
5
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| SMILES |
CCNC(=O)CCC/C=C\C[C@H]1[C@H](C[C@H]([C@@H]1/C=C/[C@H](CCC2=CC=CC=C2)OC(=O)CCCCCO[N+](=O)[O-])O)O
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| InChi Key |
NTQMJNDRYSYWNJ-BPXWCPHMSA-N
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| InChi Code |
InChI=1S/C31H46N2O8/c1-2-32-30(36)16-10-4-3-9-15-26-27(29(35)23-28(26)34)21-20-25(19-18-24-13-7-5-8-14-24)41-31(37)17-11-6-12-22-40-33(38)39/h3,5,7-9,13-14,20-21,25-29,34-35H,2,4,6,10-12,15-19,22-23H2,1H3,(H,32,36)/b9-3-,21-20+/t25-,26+,27+,28-,29+/m0/s1
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| Chemical Name |
[(E,3S)-1-[(1R,2R,3S,5R)-2-[(Z)-7-(ethylamino)-7-oxohept-2-enyl]-3,5-dihydroxycyclopentyl]-5-phenylpent-1-en-3-yl] 6-nitrooxyhexanoate
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 100 mg/mL (174.00 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7400 mL | 8.7000 mL | 17.4001 mL | |
| 5 mM | 0.3480 mL | 1.7400 mL | 3.4800 mL | |
| 10 mM | 0.1740 mL | 0.8700 mL | 1.7400 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Link: https://clinicaltrials.gov/ct2/show/NCT05938699
Conditions:Open Angle GlaucomaLink: https://clinicaltrials.gov/ct2/show/NCT04445519
Conditions:Open Angle Glaucoma|Ocular HypertensionLink: https://clinicaltrials.gov/ct2/show/NCT03657797
Conditions:Glaucoma, Open-Angle|Hypertension, OcularProducts are for research use only; We do not sell to patients
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