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Purity: ≥98%
Acrizanib, formerly known as LHA510, is a novel, potent and selective angiogenesis inhibitor and VEGFR‑2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular Degeneration.
| Targets |
VEGFR-2 (KDR) – cellular IC50 in BaF3-Tel-KDR proliferation assay: 17 nM (mean cellular IC50) [1]
Kinase selectivity: screened against 442 kinases at 1 μM; exhibited ≤10% remaining kinase activity against only 13 wild-type kinases: CSF1R, Kit, PDGFRα, PDGFRβ, VEGFR1, VEGFR2, VEGFR3, Fms (soluble VEGFR1), DDR1, DDR2, TIE1, and ABL1 (nonphosphorylated) [1] |
|---|---|
| ln Vitro |
The VEGFR-2 inhibitor acizanib has an IC50 for BaF3-KDR of 17.4 nM. Merely thirteen wild-type kinases were demonstrated to be susceptible to ≤10% residual kinase activity by Acrizanib (Compound 35): CSF1R, Kit, PDGFRα, PDGFRβ, VEGFR1, VEGFR2, VEGFR3, Fms (soluble VEGFR1), DDR1, DDR2, TIE1, and ABL1 (non-phosphorylated) [1].
Cellular potency: Acrizanib inhibited BaF3-Tel-KDR cell proliferation with a mean IC50 of 17 nM. These cells are engineered to constitutively require VEGFR-2 kinase domain activity for survival. [1] Kinase selectivity: In an external commercial kinase panel (AMBIT, KINOMEScan) at a screening concentration of 1 μM against 442 kinases, acrizanib showed ≤10% remaining kinase activity for only 13 wild-type kinases, including VEGFR2, VEGFR1, VEGFR3, PDGFRα, PDGFRβ, Kit, CSF1R, Fms, DDR1, DDR2, TIE1, and ABL1. [1] |
| ln Vivo |
Studies on the ocular PK of acrizanib in rats revealed notable distinctions from those found with compound 25. The AUC ratio to acrizanib levels in plasma increased significantly (higher in PEC than in plasma at day 11), despite the fact that long-term exposure was evident in PEC once more. Furthermore, 10 days after administration, acrizanib significantly improved, in contrast to 25, the retinal to plasma AUC exposure ratio (598× for acrizanib vs. 0.8× for 25) [1].
Rat CNV model: Acrizanib (4 μL × 1.0% suspension/eye, tid) achieved 90% inhibition of neovascular area in the laser-induced choroidal neovascularization (CNV) model using Brown Norway rats. [1] Dose-response in rat CNV model: ED50 and ED90 values determined for different dosing frequencies – qd: ED50 = 1.4%, ED90 = not determined; bid: ED50 = 1.0%, ED90 = 2.6%; tid: ED50 = 0.5%, ED90 = 1.2% (formulation: suspension, 4 μL/eye). [1] Mouse CNV model: Methylation of the pyrazole nitrogen of compound 34 to afford acrizanib led to full inhibition of neovascularization in the mouse CNV model. [1] Rabbit ocular PK (direct delivery assessment): After unilateral topical administration (2% suspension, 30 μL, tid for 7 days) to NZW × NZR F1 pigmented rabbits, the delta exposure between dosed and undosed eyes indicated that 37% of the AUC within the RPE/choroid and 57% of the AUC within the retina could be attributed to direct delivery from the eye drop. [1] |
| Enzyme Assay |
Kinase selectivity profiling was performed using a commercial external kinase panel (AMBIT, KINOMEScan). Acrizanib was screened at a concentration of 1 μM against 442 wild-type kinases. The percentage of remaining kinase activity was measured, and compounds exhibiting ≤10% remaining activity were considered hits. The assay identified that acrizanib had ≤10% remaining activity against only 13 wild-type kinases: CSF1R, Kit, PDGFRα, PDGFRβ, VEGFR1, VEGFR2, VEGFR3, Fms (soluble VEGFR1), DDR1, DDR2, TIE1, and ABL1 (nonphosphorylated). [1]
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| Cell Assay |
The BaF3 proliferation assay was used to evaluate cellular potency against VEGFR-2. BaF3-Tel-KDR cells are engineered to constitutively require VEGFR-2 kinase domain activity for survival. The assay protocol has been previously described (see reference 28 in the paper). The mean cellular IC50 of acrizanib in this assay was determined to be 17 nM. [1]
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| Animal Protocol |
Rat CNV model: Laser-induced choroidal neovascularization was performed in Brown Norway rats. Compounds were administered via topical ocular instillation of 4 μL drops to both eyes, three times a day (tid), using suspension formulations at various concentrations (e.g., 1.0%). Neovascular area was assessed 10-12 days post-laser, and percent inhibition was calculated by comparing lesion size in treated versus control animals. [1]
Mouse CNV model: C57BL/6 mice were used. The area of laser-induced neovascular lesion was measured 5-7 days post-laser, with compounds dosed throughout that period (3.5 μL/eye, tid). [1] Rat ocular PK study: Brown Norway rats received topical ocular dosing of acrizanib (4 μL × 0.3% suspension/eye, tid) for 10 days; on day 11, a single dose was given and PK parameters were assessed over 24 hours. Tissues (retina, posterior eye cup PEC) and plasma were collected. [1] Cynomolgus monkey plasma PK study: Monkeys received topical ocular dosing of acrizanib (30 μL × 1.0% /eye, qd) as both an optimized solution formulation and a suspension formulation. Plasma samples were collected to determine PK parameters. [1] Rabbit ocular PK study: Eight- to twelve-month-old New Zealand White × New Zealand Red F1 rabbits (2-4 kg) were administered acrizanib via topical ocular instillation (2% suspension, 30 μL, tid for 7 days) to only one eye. Ocular tissues (retina and RPE/choroid) from both dosed and undosed eyes, as well as plasma, were collected at 0.5, 1, 3, 6, 18, 48, and 96 hours after the last instillation. Drug concentration was analyzed by LC-MS/MS after homogenization, protein precipitation, and liquid/liquid extraction. [1] |
| ADME/Pharmacokinetics |
at ocular PK after topical administration (4 μL × 0.3% suspension/eye, tid): On day 11, posterior eye cup (PEC) mean AUC(0-last) = 15,000 nM·h, retina mean AUC(0-last) = 14,300 nM·h, plasma mean AUC(0-last) = 24.4 nM·h; PEC/plasma AUC ratio >21,000-fold; retina/plasma AUC ratio = 598-fold. Cmax in PEC = 31,800 nM, retina = 1,910 nM, plasma = 32.1 nM. [1]
Cynomolgus monkey plasma PK after single dose (30 μL × 1.0% /eye, qd): Solution formulation – AUC0-6h = 64.4 ± 17.1 nM·h, Cmax = 26.9 ± 5.9 nM, T1/2 = 1.61 ± 0.31 h, Tmax = 0.67 ± 0.29 h. Suspension formulation – AUC0-6h = 22.7 ± 6.70 nM·h, Cmax = 65.3 ± 81.0 nM, T1/2 = 4.38 ± 1.21 h, Tmax = 1.67 ± 1.15 h. [1] Melanin binding affinity: Acrizanib showed Bmax1 and Bmax2 values of 368 and 134 nmol/mg, respectively, and Kd1 and Kd2 values of 6.4 and 0.56 μM (conditions as described in reference 40 of the paper). Prolonged ocular exposure is attributed in part to melanin affinity. [1] Rat liver microsomal intrinsic clearance (RLM Clint): Although not explicitly stated for acrizanib, the structurally related compound 34 (which differs by methylation of the pyrazole nitrogen to give 35) exhibited a high RLM Clint of 156 μL/min/mg, and acrizanib maintained a very high RLM Clint. [1] |
| Toxicity/Toxicokinetics |
Ocular tolerability in cynomolgus monkeys after 5 days of topical dosing (30 μL × 0.5% suspension/eye, tid, equivalent to ~0.3 mg/kg per day) was acceptable with no adverse ocular events noted (anterior and adnexa regions examined by slit lamp biomicroscope, ocular fundus by indirect ophthalmoscope). [1]
Acrizanib possesses an acceptable toxicology profile, assessed in part by GLP studies involving topical ocular administration to cynomolgus monkeys and NZW × NZR F1 rabbits, as well as oral dosing in Wistar-Han rats. [1] |
| References | |
| Additional Infomation |
Acrizanib is being investigated in the clinical trial NCT02355028 (LHA510 proof-of-concept study, as maintenance therapy for patients with wet age-related macular degeneration).
Neovascular age-related macular degeneration (wet AMD). [1] Mechanism of action: VEGFR-2 inhibitor that suppresses pathological choroidal neovascularization by blocking VEGF-A signaling through VEGFR-2 on endothelial cells. [1] Design strategy: Specifically designed for topical ocular delivery to the back of the eye, overcoming challenges of tear film, corneal barriers, and blood-retinal barrier, while minimizing systemic exposure and on-target toxicity. [1] Formulation: Multiple formulation options, including a 1% solution formulation near the ED90 with tid dosing. [1] Clinical evaluation: Selected for clinical evaluation; clinical trials employing topical ocular administration of acrizanib were registered under ClinicalTrials.gov identifiers NCT02076919 and NCT02355028. [1] |
| Molecular Formula |
C20H18F3N7O2
|
|---|---|
| Molecular Weight |
445.397833347321
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| Exact Mass |
445.147
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| CAS # |
1229453-99-9
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| Related CAS # |
1229453-99-9;
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| PubChem CID |
59394698
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
32
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| Complexity |
655
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C1=CC(=NN1C)NC(N1C=CC2C=C(C=CC1=2)OC1C=C(CNC)N=CN=1)=O)(F)F
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| InChi Key |
XPIHPLVWOUDMPF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H18F3N7O2/c1-24-10-13-8-18(26-11-25-13)32-14-3-4-15-12(7-14)5-6-30(15)19(31)27-17-9-16(20(21,22)23)29(2)28-17/h3-9,11,24H,10H2,1-2H3,(H,27,28,31)
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| Chemical Name |
5-({6-[(methylamino)methyl]pyrimidin-4-yl}oxy)-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-1H-indole-1-carboxamide
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| Synonyms |
Acrizanib LHA510 LHA 510 LHA-510.
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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 |
| 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 : ~41.67 mg/mL (~93.56 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.67 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.67 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.67 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2452 mL | 11.2259 mL | 22.4517 mL | |
| 5 mM | 0.4490 mL | 2.2452 mL | 4.4903 mL | |
| 10 mM | 0.2245 mL | 1.1226 mL | 2.2452 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02076919 | Completed Has Results | Drug: LHA510 Ophthalmic Suspension Drug: LHA510 Vehicle |
Age-Related Macular Degeneration | Alcon Research | February 2014 | Phase 1 |
| NCT02355028 | Completed Has Results | Drug: LHA510 ophthalmic suspension Drug: LHA510 vehicle |
Exudative Age-Related Macular Degeneration |
Alcon, a Novartis Company | March 3, 2015 | Phase 2 |
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