Bezisterim, HE 3286; NE-3107

Bezisterim, HE 3286; NE-3107

CAS 1001100-69-1

(1R,3aS,3bR,4R,7S,9aR,9bS,11aS)-1-ethynyl-9a,11a-dimethyl-1H,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthrene-1,4,7-triol

• (3β,7β,17α)-Pregn-5-en-20-yne-3,7,17-triol
• 17α-Ethynyl-5-androstene-3β,7β,17β-triol
• 17α-Ethynyl-Δ⁵-androstene-3β,7β,17β-triol
• 17α-Ethynylandrost-5-ene-3β,7β,17β-triol
• 3β,7β,17β-Trihydroxy-17α-ethynylandrost-5-ene
• Bezisterim
• HE 3286
• NE 3107
• Triolex

(3S,7R,8R,9S,10R,13S,14S,17R)-17-ethynyl-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-3,7,17-triol

• Pregn-5-en-20-yne-3,7,17-triol, (3beta,7beta,17alpha)-
• PH8858757I
• UNII-PH8858757I

• (1R,3aS,3bR,4R,7S,9aR,9bS,11aS)-1-ethynyl-9a,11a-dimethyl-1H,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta(a)phenanthrene-1,4,7-triol
• (1R,3aS,3bR,4R,7S,9aR,9bS,11aS)-1-ethynyl-9a,11a-dimethyl-1H,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthrene-1,4,7-triol
• 17-ethynyl-5-androstene-3, 7, 17-triol

Bezisterim (developmental code names NE3107, HE3286) is a synthetic analogue of androstenetriol that is believed to have anti-inflammatory and insulin-sensitizing effects in the brain.^[1] The compound crosses the blood–brain barrier and does not activate any neurotransmitter receptors.^[2] It has been tested as a treatment for Alzheimer’s disease,^[3][4][5][6] Parkinson’s disease,^[1] and traumatic brain injury.^[7] The drug is under development for a variety of conditions and its highest developmental phase is phase 3 for Alzheimer’s disease.^[1]

• Originator Hollis-Eden Pharmaceuticals
• Developer BioVie; Harbor Therapeutics; National Institutes of Health (USA); NeurMedix
• Class Anti-inflammatories; Antidementias; Antiepileptic drugs; Antifibrotics; Antiglaucomas; Antihyperglycaemics; Antimigraines; Antineoplastics; Antiparkinsonians; Antirheumatics; Hormones; Insulin sensitisers; Nootropics; Obesity therapies; Small molecules
• Mechanism of Action Adiponectin stimulants; Interleukin 23 inhibitors; Interleukin 6 inhibitors; Mitogen-activated protein kinase 1 inhibitors; Mitogen-activated protein kinase 3 inhibitors; NF-kappa B inhibitors; Tumour necrosis factor inhibitors

• Cystic fibrosis

• Phase III Alzheimer’s disease
• Phase II Parkinson’s disease; Traumatic brain injuries
• Preclinical Multiple myeloma; Prostate cancer
• No development reported Drug-induced dyskinesia
• Discontinued Amyotrophic lateral sclerosis; Cognition disorders; Cystic fibrosis; Epilepsy; Glaucoma; Huntington’s disease; Migraine; Myositis; Optic neuritis; Rheumatoid arthritis; Type 1 diabetes mellitus; Type 2 diabetes mellitus; Ulcerative colitis; Uveitis

28 Feb 2025BioVie plans the phase II ADdRESs-LC trial for Post-acute COVID-19 syndrome in USA (PO, Capsule), in February 2025 (NCT06847191)

• 18 Feb 2025Phase-II clinical trials in Parkinson’s disease (Early-stage disease, In the elderly) in USA (PO) (NCT06757010)
• 03 Jan 2025BioVie plans a phase II SUNRISE-PD trial for Parkinsons disease (Early stage disease) in February 2025 (PO) (NCT06757010)

SCHEME

US20100227841 

https://patentscope.wipo.int/search/en/detail.jsf?docId=US43352763&_cid=P11-M9JSD6-84971-1

17α-Ethynylandrost-5-ene-3β,7β,17β-triol was prepared as follows

US20100222315  https://patentscope.wipo.int/search/en/detail.jsf?docId=US43344622&_cid=P11-M9JSIE-88638-1

WO2009149392

PATENT’

WO2009149392

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009149392&_cid=P11-M9JSL7-90448-1

49] Example 7. Synthesis of 3β-acetoxy-androst-5-ene-17,17-ethylenedioxy: A 300L reactor was charged with 36 kg of triethylorthoformate, 20 kg of 3β-acetoxy-5-androsten-17-one, 12.6 kg of ethylene glycol and 400 g of p-toluenesulfonic acid. The mixture was heated to reflux under nitrogen until the reaction was complete (about 2-3 hours). The mixture was then cooled to 60 ⁰C and 16 kg of anhydrous ethanol and 400 ml of pyridine were added. The resulting solution was transferred to a container and refrigerated overnight. The solids that formed were filtered and washed with 80 kg of 50% ethanol and dried at 40-50 ⁰C to afford 18.5-21.0 kg (81.5-92.5%) of the title compound. [50] Example 8. Synthesis of 3β-acetoxy-androst-5-en-7-one-17,17-ethylenedioxy: A 500 L reactor was charged with 200 kg ethyl acetate and 25 kg of 3β-acetoxy-androst-5-en-17,17-ethylenedioxy. The mixture was stirred for 30 minutes whereupon 55 kg of 70% t-butyl peroxide and 9 kg of sodium bicarbonate were added. The reaction mixture was then cooled to 0 ⁰C and 116 kg of 13% sodium perchlorate (aq.) was added over 10 hours so that a reaction temperature below 5 ⁰C and pH between 7.5 and 8.5 were maintained. After the reaction was complete, the organic layer was separated and the aqueous phase was extracted with ethyl acetate (35 kg x 2). The combined organic phase was combined with a solution 33 kg of sodium sulfite in 167 kg of water, and the resulting mixture was stirred at 40 ⁰C for 3 hours. The organic phase was washed with 50 kg of brine and concentrated to 55-60 kg whereupon 50 kg of methanol was added. After refrigeration overnight, a white solid was formed that was filtered and washed with 10 kg of methanol, and dried at 40-50 ⁰C to yield 7.1-7.8 kg (27.4-30.1%) of the title compound.

[51] Example 9. Synthesis of 3β-acetoxy-androst-5-ene-17,17-ethylenedioxy-7β-ol. A 500 L reactor was charged with 48 kg of THF, 10 kg of 3β-acetoxy-androst-5-en-7-one-17,17-ethylenedioxy and a solution of 9.6 kg CeCI₃-7H₂O in 95 kg methanol. This mixture was cooled to 0 ⁰C whereupon 2.0 kg of NaBH₄ was added in batches over 3 hours in order to maintain the temperature below 5 ⁰C. After stirring for 30 more minutes, 28 kg of acetone was added slowly in order to maintain the temperature below 5 ⁰C, with stirring continued for another 30 minutes. To the mixture was added 240 kg water with stirring continued for 1 hour. The organic solvents were removed under vacuum and the residue was extracted with ethyl acetate (100 kg + 50 kg). The combined organic phase was washed with brine. Solvent was then removed to provide 8.6-8.9 kg (85.1-88.1 %) of the title compound. [52] Example 10. Synthesis of 3β-acetoxy-androst-5-en-17-one-7β-ol: A 500 L reactor was charged with 315 kg of acetone and 18 kg of 3β-acetoxy-androst-5-en-17,17-ethylenedioxy-7β-ol. The mixture was cooled to 5 ⁰C and 2.34 kg of p-toluenesulfonic acid was added slowly to maintain the temperature below 10 ⁰C. After stirring the mixture at 8-15 ⁰C for 36-48 hours, 3.0 kg of sodium bicarbonate was added with stirring continued for 1 hour. Acetone was removed under vacuum, and to the residue was added 100 kg of water. The mixture was placed in a refrigerator overnight to give a white precipitate which was filtered to provide 33 kg (wet) of the title compound.

[53] Example 11. Synthesis of androst-5-en-17-one-3β,7β-diol: A 500 L reactor was charged 230 kg methanol, 33 kg (wet) 3β-acetoxy-7β-hydroxy-5-androsten-17-one, 108 kg water and 15 kg NaaCOβ. The mixture was heated to reflux for 3 hours. Methanol was removed under vacuum whereupon 250 kg of water was added to the residue. The mixture was put in refrigerator overnight to give a precipitate. The solids were collected by filtration, then washed with water and dried at 40-50 ⁰C to yield 9.5-10.5 kg (67.9-75.0%) of the title compound as a white solid.

[54] Example 12. Purification of androst-5-en-17-one-3β,7β-diol: A 500 L reactor was charged with 20 kg crude 3β, 7β-dihydroxyandrost-5-en-17-one and 200 kg methanol and heated until all the solid dissolved. The solution was filtered while hot and after the filtrate cooled a white crystalline solid formed. The solids were collected by filtration, washed with small amount of methanol and dried at 40-50 ⁰C. The solid was then refluxed in 50 kg of ethyl acetate for 20 minutes. After cooling the solid was filtered and dried at 40-50 ⁰C under vacuum to provide 15.2 kg (76%) of purified title compound.

[55] Example 13. Synthesis of 3β,7β-bis-(trimethylsiloxy)-5-androsten-17-one: A mixture of 14.87 Kg of androst-5-en-17-one-3β,7β-diol, 23.8 Kg HMDS and 0.7 Kg saccharin catalyst in 100 L acetonitrile was heated to reflux for 8 hours with stirring under a nitrogen atmosphere. Liberated ammonia was purged under slight vacuum. The reaction volume was then reduced by distillation to collect 3OL of distillate (requires about 2 h). The reaction volume was further reduced to half of the original reaction volume by distillation under reduced pressure (700 mmHg), which requires about 2h of heating at 50 ⁰C. The resulting uniform thick slurry is cooled to 5 ⁰C (requires about 3 h), with additional acetonitrile added to maintain a minimum mixing volume, and held at that temperature for 1. The precipitated product was collected by filtration and dried at 45-50 ⁰C under vacuum (29 mmHg) to a loss on drying (LOD) of not more than 1 % (requires 20 h) to provide 16 Kg (81 % yield) of the title compound (95% purity). [56] Example 14. Synthesis of 17α-ethynyl-5-androstene-3β,7β,17β-triol: To 11.02 Kg TMS-acetylene in 56.5 L tetrahydrofuran (THF) at -27 ⁰C under a nitrogen atmosphere was added 8.51 L 10M n-BuLi. The n-butyl lithium was added very slowly to maintain a temperature at -7 to -27 ⁰C (requires about 2 h) and the resulting reaction was stirred 10 min. at approximately 0°C to produce TMS-lithium-acetylide. To the TMS-lithium-acetylide solution was added a solution of 25.41 Kg of 3β,7β-bis-(trimethylsiloxy)-5-androsten-17-one in 95.3 L THF filtered through a 25 μm filter while allowing the reaction temperature to rise to 20-25 ⁰C. After addition was completed, the reaction temperature was increased to 40-45 ⁰C. To quench the reactor contents, 31.8 L of methanol was added over a period of about 1 h followed by 3.81 Kg KOH in 18.4 L of water giving a final reactor temperature of 50 ⁰C. Liberated acetylene is purged under slight vacuum. The reactor contents were then concentrated by distillation at 80 ⁰C for 1 h then under vacuum (175 mmHg) at about 70 ⁰C (with an initial temperature of 25 ⁰C to avoid bumping) to half of the original pot volume. The residue was cooled to about 10 ⁰C and 35.0 Kg of deionized water was added, followed by 16.4 Kg 12N HCI while maintaining a pot temperature of about 10 ⁰C and giving a final pH of 1. Additional 26.0 kg deionized water was added and the resulting mixture was stirred at about 5 ⁰C for 1 h. The resulting slurry was filtered and washed with 75/25 mixture of methanol/water (16.9 L methanol, 5.6 L water). The collected solids were dried under vacuum (28 in Hg) at 45 ⁰C for 12h for a loss on drying of no more than 0.5% to provide 9.6 Kg of the title compound (83% yield).

[57] Example 15. Recrystallization of 17α-ethynyl-5-androstene-3β,7β,17β-triol: Crude 9.6 Kg 17α-ethynyl-5-androstene-3β,7β,17β-triol prepared in

Example 14 was dissolved in refluxing 50/50 methanol/water (4.2 Kg methanol and 5.4 Kg water). To the solution was added 33.4 Kg methanol followed by 37.6 Kg of THF. The mixture was heated to reflux and stirring was continued until all solids have dissolved, whereupon 99.8 Kg of deionized water was added while maintaining a reactor temperature of 60-75 ⁰C. The mixture was cooled to 0-5 ⁰C over a period of 2 h and maintain at that temperature for 1 h while stirring was continued. The solids were recovered by filtration, washed with 9.6 Kg cold 50/50 methanol water and dried under vacuum (28 in Hg) at 50 ⁰C for 8 h to provide 8.2 Kg of 17α-ethynyl-5-androstene-3β,7β,17β-triol. This first recrystallization is used to remove trace colored impurities from the initial product. A second recrystallization was conducted by heating the solid from the first recrystallization in ~10:1 methanohwater (145.8 Kg methanol and 18.2 Kg of water) to 80°C until all the solids have dissolved. The solution at 55-60 ⁰C was filtered through a 25 μm filter to remove particulate impurities, whereupon 2.5 Kg of methanol at 55-60 ⁰C (used to rinse the reactor) was added. Vacuum distillation at 125 mmHg at 70 ⁰C was conducted until 0.9 to 1.2 times the volume of methanol that was added to the reactor was collected as distillate with water added as necessary to permit stirring (about 120-160 Kg water added). Final reaction volume was 200-225 L. The reactor mixture was cooled to 0-5 ⁰C and maintained at that temperature for 1 h. The resulting slurry was filtered and the filter cake rinsed with 10 Kg deionized water and dried under vacuum (28 in Hg) at 50 ⁰C for 12 h to a residual water content of less than 0.5%. This isolation procedure was used to reduce the THF content in the final product. The yield was 8.0 Kg of recrystallized title compound (83% yield).

[59] Example 16. Synthesis of 3β-acetoxy-androst-5-en-7-on-17-oxime: 3β-Acetoxy-androst-5-en-7,17-dione (45 g, 130 mmol) was dissolved in 800 ml_ methanol, 200 ml_ dichloromethane and 14.5g Et₃N (144 mmol). To the solution at RT was added a solution of 10 g of hydroxylamine hydrochloride dissolved in 200 ml_ methanol. After stirring overnight, 200 ml_ of water was added followed by removal of volatile organics by evaporation under reduced pressure. To the resulting residue was added an additional 1 L of water to give a while solid that was filtered and washed well with water. Obtained was 45 g of crude title oxime in 95% purity by ¹H-NMR, which was used in the next step without further purification.

[60] Example 17. Synthesis of 3β-acetoxy-androst-5-en-17-oxime-7β-ol: To a solution of 44 g of 3β-acetoxy-androst-5-en-7-on-17-oxime (100 mol%) in 800 ml_ methanol and 200 ml_ tetrahydrofuran was added 50 g of cerium chloride heptahydrate (110 mol%) in 20 ml_ of methanol. The resulting mixture was stirred until the solids were completely dissolved. To the solution cooled to about -5 ⁰C was added 7 g sodium borohydride over 30 min. After stirring an additional 1.5 h at -5 ⁰C, the reaction mixture was quenched with acetone (100 mL) and then allowed to warm to room temperature over a 30 min. period. The quenched reaction mixture was concentrated under vacuum to remove volatile organics. To the residue was added 800 mL of water followed by extraction with ethyl acetate (3 x 500 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄, then concentrated to provide 42 g of the title compound as a white foam, which was used in the next step without further purification.. [61] Example 18. 3β-acetoxy-androst-5-en-17-one-7β-ol: To a solution of 42 g of 3β-acetoxy-androst-5-en-17-oxime-7β-ol (100 mol%) in 200 mL of ethanol was added 100 mL of water followed by 80 g (400 mol%) of sodium dithionite. The reaction was heated at 55 ⁰C and stirred 16 h. After cooling, the reaction was concentrated under reduced pressure. The residue was diluted with 100 mL of water, and the resulting solid was collected by filtration and redissolved in 1 L dichloromethane. To the DCM solution was added 1 g activated carbon. After stirring overnight the mixture was filtered, and the resulting filtrate was washed with water, dried and concentrated to provide 25 g of crude product. Recrystallization from ethyl acetate gave 22g of the title compound. [62] Example 19. Estrogen receptor binding assay: A suitable example system is an estrogen receptor- kit manufactured by PanVera for ERβ, which contains recombinant estrogen receptor β ligand, FLUORMONE ES2 (ES2), a fluorescently labeled estrogen ligand, and appropriate buffer. The system was used in a fluorescence polarization competition assay in which a test article, such as a preparation of Compound 1 or a positive control displaces ES2 from its binding site. When bound to ERβ, ES2 tumbles slowly and has a high fluorescence polarization value. Unbound ES2 tumbles quickly and displays a low fluorescence polarization value. The change in polarization value in the presence of test compound then determines relative binding affinity of that test compound for ERβ as expressed by its IC_50, which is the concentration of test compound that results in half-maximum shift in polarization. From IC₅₀, K_/ was calculated using the Cheng-Prusoff equation [Biochem. Pharmacol. 22: 3099-3108, (1973)]: K, = IC₅₀Z(I + D/K_d) where D is the concentration of ES2 and K_d is the dissociation constant for binding of ES2 to ERβ (K_d = 4 ± 2 nM).

[63] The competition assay was conducted according to the manufacturer’s protocol (Lit. No. L0712, Rev. 10/03). Assay reagents used were bacculovirus expressed, full length human ERβ 4.5 pmol/μL in 50 mM Bis-Tris Propane (pH = 9), 400 mM KCI, 2 mM DTT, 1 mM EDTA, 10% glycerol, ES2 400 nM in methanol and E2 screening buffer consisting of 100 mM potassium phosphate (pH = 7.4), 100 μg/mL BGG, 0.02% NaN₃. The ES2-ERβ complex was formed with 20 μL 20 nM ERβ (0.020 pmol/μL) and 20 μl_ 2 nM ES2 (0.002 pmol/μL). Positive control (estrogen) solution was prepared using 20 μL of a 1.0 mM stock solution in DMSO and 80 μL DMSO. In a first dilution, 50 μL of this solution is added to 50 μL of DMSO, which is followed by dilutions in 2-fold increments, to provide for a 14 point dilution curve. In a second dilution, to 4 μL of each DMSO solution from the first dilution is added 400 μL of ES2 screening buffer. To 20 μL of test compound, serially diluted in the manner described immediately above, in a 384 well black flat bottom microtiter plate, was added 20 μL of the ES2-ERβ complex (0.5% final DMSO concentration) followed by incubation in the dark at 20-30 ⁰C for 1-4 h. Test compound was treated similarly except the starting concentration was 10 mM. Fluorescence polarization values are obtained using 485 nm excitation and 530 nm emission interference filters. Binding assay for ERa was conducted as for ERβ except bacculovirus expressed, full length human 2.8 pmol/μL ERa was used as reagent with the ERα-ES2 complex formed from 20 μL 30 nM (0.030 pmol/μL) and 20 μL 2 nM ES2 (0.002 pmol/μL). [64] Example 20. AR, GR and PR receptor binding assays. The AR competition assay was conducted according to the manufacturer’s protocol (Lit. No. L0844, Rev. 05/02) in the manner described for ERβ with the following exceptions. Reagents used were recombinant rat androgen receptor ligand binding domain tagged with His and GST [AR-LBD (His-GST)] 0.38 pmol/μL in buffer containing protein stabilizing agents and glycerol (pH = 7.5), 200 nM FLUORMONE AL Green, which is a fluorescently labeled androgen ligand, in 20 mM Tris, 90% methanol and AR screening buffer containing stabilizing agents and glycerol (pH = 7.5) with 2 μL of 1 mM DTT added per mL screening buffer (AR screening buffer 2 mM in added DTT) was used as the reagents. The AL Green-AR complex was formed with 20 μL 50 nM AR (0.050 pmol/μL) and 20 μL 2 nM AL Green (0.002 pmol/μL). K, was calculated using, for the dissociation constant for binding of the fluorophore to receptor, K_d = 20 ± 10 nM. [65] The PR competition assay was conducted according to the manufacturer’s protocol (Lit. No. L0503, Rev. 06/03) in the manner described for ERβ with the following exceptions. Reagents used were recombinant human progesterone receptor ligand binding domain tagged with GST [PR-LBD (GST)] 3.6 pmol/μL in 50 mM Tris (pH = 8.0), 500 mM KCI, 1 M urea, 5 mM DTT, 1 mM EDTA and 50% glycerol, 400 nM FLUORMONE PL Green, which is a fluorescently labeled progesterone ligand, in 20 mM Tris 90% methanol (pH = 6.8) and PR screening buffer containing protein stabilizing agents and glycerol (pH = 7.4) with 4 μL of 1 mM DTT added per mL screening buffer (PR screening buffer 4 mM in added DTT). The PL Green-PR complex was formed with 20 μL 80 nM PR (0.080 pmol/μL) and 20 μL 4 nM PL Green (0.004 pmol/μL). K, was calculated using, for the dissociation constant for binding of the fluorophore to receptor, K_d = 40 nM.

[66] The GR competition assay was conducted according to the manufacturer’s protocol (Lit. No. L0304, Rev. 12/01) in the manner described for ERβ with the following exceptions. Reagents used were recombinant full length human glucocorticoid receptor 0.240 pmol/μL in 10 mM phosphate buffer (pH = 7.4), 200 mM Na₂MoO₄, 0.1 mM EDTA, 5 mM DTT and 10% glycerol, 200 nM FLUORMONE GS1 , which is a fluorescently labeled glucocorticoid ligand, in 75% methanol, and GR screening buffer containing 100 mM potassium phosphate (pH = 7.4), 200 mM Na₂MoO_4, 1 mM EDTA, 20% DMSO with 5 μL of 1 mM DTT per mL screening buffer added (GR screening buffer 5 mM in added DTT), 1 mM GR stabilizing peptide, which is a co-activator related peptide [see Chang, CY. MoI. Cell Biol. 19: 8226-36 (1999)] in 10 mM phosphate buffer (pH = 7.4) and 1 M DTT in water were used as the reagents. To 2.5 mL of the GR screening buffer is added 2.5 mL GR stabilizing peptide solution and 125 μL of 1 M DTT to form the GR stabilizing peptide-glucocorticoid receptor complex. Order of addition to the microtiter plate was 20 μL test compound in 1 % DMSO, 10 μL of 16 nM GR (0.016 pmol/μL) and finally 10 μL of 4 nM GS1 , followed by incubation in the dark at 20-30 ⁰C for 4 h (total experiment time should not exceed 7 h). K, was calculated using, for the dissociation constant for binding of the fluorophore to receptor, K_d = 0.3 ± 0.1 nM.

[67] Example 21. Impurity profiling of 17α-ethynyl-5-androstene-3β,7β,17β- triol (Compound 1) preparations.

[68] Process A: HPLC conditions for Impurity profiling of Compound 1 preparations form Process B are give in Table 1.

[69]

Table 1. HPLC Conditions for Impurity Profiling of Compound 1 Preparations form Process A

PATENT

Hollis-Eden Pharmaceuticals, Inc. WO2008039566 

Zhejiang Xianju Junye Pharmaceutical Co., Ltd.; Jiangxi Junye Biopharmaceutical Co., Ltd.CN114478672

Harbor BioSciences, Inc.US20100227841

Harbor BioSciences, Inc. US20100222315 A1

Hollis-Eden Pharmaceuticals, Inc. US20100075937

Neurmedix Inc. US20080153792 A1

Hollis-Eden Pharmaceuticals, Inc.; Harbor Therapeutics, Inc. US20080146532 A1 

Harbor Therapeutics, Inc.; Neurmedix, Inc. US20160045516 A1

 Harbor Therapeutics, Inc. US8354396 B2 

Hollis-Eden Pharmaceuticals, Inc. WO2009149392

References

1. ^ Jump up to:^a b c “Bezisterim”. AdisInsight. 5 September 2024. Retrieved 26 September 2024.
2. ^ Reading, Chris L; Ahlem, Clarence N; Parameswaran, Narayanan (December 2021). “Rationale for an anti-inflammatory insulin sensitizer in a phase 3 Alzheimer’s disease trial”. Alzheimer’s & Dementia. 17 (S9). doi:10.1002/alz.057438.
3. ^ Stoiljkovic, Milan; Horvath, Tamas L.; Hajós, Mihály (July 2021). “Therapy for Alzheimer’s disease: Missing targets and functional markers?”. Ageing Research Reviews. 68: 101318. doi:10.1016/j.arr.2021.101318. PMC 8131215. PMID 33711510.
4. ^ Balzano, Tiziano; Esteban-García, Noelia; Blesa, Javier (2 January 2023). “Neuroinflammation, immune response and α-synuclein pathology: how animal models are helping us to connect dots”. Expert Opinion on Drug Discovery. 18 (1): 13–23. doi:10.1080/17460441.2023.2160440. PMID 36538833. S2CID 254959175.
5. ^ Liu, Ping; Wang, Yunyun; Sun, Yan; Peng, Guoping (April 2022). “Neuroinflammation as a Potential Therapeutic Target in Alzheimer’s Disease”. Clinical Interventions in Aging. 17: 665–674. doi:10.2147/CIA.S357558. PMC 9064449. PMID 35520949.
6. ^ Xi, Yilong; Chen, Yun; Jin, Yi; Han, Guochen; Song, Mingjie; Song, Tingting; Shi, Yang; Tao, Ling; Huang, Zewei; Zhou, Jianping; Ding, Yang; Zhang, Huaqing (May 2022). “Versatile nanomaterials for Alzheimer’s disease: Pathogenesis inspired disease-modifying therapy”. Journal of Controlled Release. 345: 38–61. doi:10.1016/j.jconrel.2022.02.034. PMID 35257810. S2CID 247285338.
7. ^ “U.S. Clinical Trial: Neurological Associates of West Los Angeles Listed a New Clinical Trial to Study Insulin-sensitizing NE3107 in Improving Sleep and Fatigue in Subjects With Traumatic Brain Injury.” Contify Life Science News, 1 Aug. 2023, p. NA. Gale OneFile: Health and Medicine, link.gale.com/apps/doc/A759542006/HRCA?u=anon~bb46c85&sid=sitemap&xid=0c315c7e. Accessed 14 Dec. 2023.

/////Bezisterim, HE 3286, NE 3107, Triolex, NE3107, NE-3107, HE3286, HE-3286, PHASE 2