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Umibecestat (CNP520; CNP-520) is an anti-AD (Alzheimer's disease) drug candidate being investigated in clinical trials. It is a novel and potent beta-secretase (BACE) inhibitor with superior BACE1/BACE2 selectivity and excellent pharmacokinetics. CNP520 reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic. The BACE-1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aβ in rats and dogs, and Aβ plaque deposition in APP-transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults ≥ 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose-dependent Aβ reduction in the cerebrospinal fluid. Thus, long-term, pivotal studies with CNP520 have been initiated in the Generation Program.
| 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].
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| 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].
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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. |
| References |
| 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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