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| Targets |
Umibecestat targets BACE1 (beta-site amyloid precursor protein cleaving enzyme-1), an aspartyl protease that cleaves amyloid precursor protein (APP) to generate amyloid-beta (Aβ) peptides. By inhibiting BACE1, umibecestat blocks the cleavage of APP, reducing the production of Aβ peptides. Aβ accumulation is a hallmark of Alzheimer's disease, making BACE1 a key therapeutic target. Umibecestat is selective for BACE-1 over other human pepsin-like aspartic proteases, including BACE-2 and cathepsin D.
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| ln Vitro |
Strong BACE-1 inhibitor umibecestat (CNP520) selectively inhibits BACE-1 as opposed to other human pepsin-like aspartic proteases, such as BACE-2 and cathepsin D [1].
In vitro, umibecestat is a potent BACE-1 inhibitor with an IC50 of 11 nM for human BACE-1. It demonstrates selectivity for BACE-1 over BACE-2 and cathepsin D. The compound's in vitro activity has been confirmed in enzymatic assays using purified BACE1 and peptide substrates. Its potency and selectivity profile support its development as a therapeutic agent for Alzheimer's disease. |
| ln Vivo |
In the rat brain and cerebrospinal fluid, umibecestat (CNP520) (1.5–51.3 mg/kg; oral gavage; 72 hours) has a long-acting, dose-dependent impact on Aβ40 [1]. After delivery, umibecestat (CNP520) (3.1 mg/kg; PO; 7 days) reduces Aβ40 and Aβ42 in cerebrospinal fluid by >75%, and during the following 7 days, the levels gradually revert to baseline [1].
In vivo, umibecestat has been evaluated in animal models of Alzheimer's disease. The compound is orally bioavailable and has been shown to reduce Aβ production in the brain and cerebrospinal fluid (CSF). In both rat brain and CSF, umibecestat has demonstrated efficacy in lowering Aβ levels. These in vivo effects support the compound's potential as a disease-modifying therapy for Alzheimer's disease. |
| Enzyme Assay |
In non-cell-based enzyme assays, umibecestat's inhibition of BACE1 is evaluated using biochemical methods. Purified BACE1 enzyme is incubated with a fluorogenic or luminescent peptide substrate that mimics the APP cleavage site, and the enzymatic activity is measured in the presence of varying concentrations of umibecestat. The compound's IC50 of 11 nM for human BACE-1 has been established using these assays. Its selectivity over BACE-2 and cathepsin D has also been confirmed.
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| Cell Assay |
In vitro cellular assays for umibecestat involve measuring its effects on Aβ production in cultured cells. Cells expressing APP are treated with umibecestat, and Aβ levels in the culture medium are measured using ELISA or other immunoassays. The compound's ability to reduce Aβ production in cellular models confirms its activity as a BACE1 inhibitor.
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| Animal Protocol |
Animal/Disease Models: Male rats (3-4 months old) [1]
Doses: 1.5 mg/kg (3 μM/kg)-51.3 mg/kg (100 μM/kg) Route of Administration: po (oral gavage); 72-hour Experimental Results: At the highest dose, Aβ40 in brain tissue diminished by 89.3±4.5%, and Aβ40 in rat brain diminished by 50% (ED50) to 2.4±0.31 mg/kg. Aβ40 in the brain and cerebrospinal fluid of rats diminished by approximately 50% 24 hrs (hrs (hours)) after a single oral dose of 30 μM/kg (15.4 mg/kg). Animal/Disease Models: 3-month-old beagle [1] Doses: 3.1 mg/kg (6 μM/kg) Route of Administration: po (po (oral gavage)) 7 days Experimental Results: 12-48 hrs (hrs (hours)) after administration, Aβ40 and Aβ42 in cerebrospinal fluid Concentrations all diminished by >75% and slowly returned to baseline over the next 7 days. In vivo animal studies for umibecestat have been conducted in rodent models. The compound is typically administered orally, and its effects on brain and CSF Aβ levels are measured. In both rat brain and CSF, umibecestat has demonstrated dose-dependent reductions in Aβ production. These studies confirm the compound's ability to penetrate the blood-brain barrier and inhibit BACE1 in the central nervous system. |
| ADME/Pharmacokinetics |
Umibecestat is orally bioavailable and has been shown to penetrate the blood-brain barrier. In both rat brain and CSF, the compound has demonstrated efficacy in reducing Aβ levels. The drug's pharmacokinetic profile supports oral administration for the treatment of Alzheimer's disease. Detailed pharmacokinetic parameters such as half-life and bioavailability are available from preclinical and clinical studies.
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| Toxicity/Toxicokinetics |
Toxicological data for umibecestat are available from preclinical studies. As a BACE1 inhibitor developed for chronic use in Alzheimer's disease, the compound has undergone extensive safety evaluation. Common adverse effects observed in clinical trials may include gastrointestinal symptoms, skin reactions, and effects on hair pigmentation. The compound's long-term safety profile continues to be evaluated in clinical trials.
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| References | |
| Additional Infomation |
Umibecestat (CNP520) is an orally bioavailable BACE1 inhibitor being developed for the prevention of Alzheimer's disease. It has IC50 values of 11 nM for human BACE-1 and 10 nM for mouse BACE-1. The compound is selective for BACE-1 over BACE-2 and cathepsin D. By inhibiting BACE1, umibecestat blocks APP cleavage and reduces Aβ production. The usage of the INN stem '-becestat' indicates that it is a beta secretase inhibitor.
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| Molecular Formula |
C19H15CLF7N5O2
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|---|---|
| Molecular Weight |
513.796527147293
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| Exact Mass |
513.08
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| Elemental Analysis |
C, 44.42; H, 2.94; Cl, 6.90; F, 25.88; N, 13.63; O, 6.23
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| CAS # |
1387560-01-1
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| Related CAS # |
1387560-01-1;2365306-62-1 (HCl);2365306-56-3 (fumarate);2365306-58-5 (tatrate);2365306-75-6 (citrate);
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| PubChem CID |
88602735
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| Appearance |
White to off-white solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
34
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| Complexity |
813
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@]1(CO[C@@](C(=N1)N)(C)C(F)(F)F)C2=C(C=CC(=N2)NC(=O)C3=C(C=C(C=N3)C(F)(F)F)Cl)F
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| InChi Key |
PSBBWFNMHDUTRH-DLBZAZTESA-N
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| InChi Code |
InChI=1S/C19H15ClF7N5O2/c1-16(7-34-17(2,15(28)32-16)19(25,26)27)13-10(21)3-4-11(30-13)31-14(33)12-9(20)5-8(6-29-12)18(22,23)24/h3-6H,7H2,1-2H3,(H2,28,32)(H,30,31,33)/t16-,17+/m0/s1
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| Chemical Name |
N-{6-[(3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl]-5-fluoropyridin-2-yl}-3-chloro-5-
(trifluoromethyl)pyridine-2-carboxamide
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| Synonyms |
CNP520 CNP-520 CNP 520
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 (~194.63 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 | 1.9463 mL | 9.7314 mL | 19.4628 mL | |
| 5 mM | 0.3893 mL | 1.9463 mL | 3.8926 mL | |
| 10 mM | 0.1946 mL | 0.9731 mL | 1.9463 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 |
| NCT03131453 | Terminated Has Results | Drug: CNP520 50mg Drug: CNP520 15mg |
Alzheimers Disease | Novartis Pharmaceuticals | August 3, 2017 | Phase 2 Phase 3 |
| NCT02576639 | Completed Has Results | Drug: CNP520 Drug: Placebo |
Alzheimer's Disease | Novartis Pharmaceuticals | August 10, 2015 | Phase 2 |
| NCT02565511 | Terminated Has Results | Biological: CAD106 Immunotherapy Other: Placebo to CAD106 |
Alzheimers Disease | Novartis Pharmaceuticals | November 30, 2015 | Phase 2 Phase 3 |
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