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Azeliragon

October 10, 2019 1:36 pm / Leave a comment

Azeliragon

C₃₂H₃₈ClN₃O₂, 532.1 g/mol

CAS 603148-36-3

TTP488

UNII-LPU25F15UQ

LPU25F15UQ

TTP-488; PF-04494700

3-[4-[2-butyl-1-[4-(4-chlorophenoxy)phenyl]imidazol-4-yl]phenoxy]-N,N-diethylpropan-1-amine

MOA：RAGE inhibitor

Indication：Alzheimer’s disease (AD)

Status：Phase III (Active), Dementia, Alzheimer’s type
Company：vTv Therapeutics (Originator)

Azeliragon

Azeliragon is in phase III clinical for the treatment of Alzheimer’s type dementia.

Azeliragon was originally by TransTech Pharma (now vTv Therapeutics), then licensed to Pfizer in 2006.

Pfizer discontinued the research in 2011, now vTv Therapeutics continues the further reaserch.

vTv Therapeutics (previously TransTech Pharma) is developing azeliragon, an orally active antagonist of the receptor for advanced glycation end products (RAGE), for the treatment of Alzheimer’s disease (AD) in patients with diabetes. In June 2019, this was still the case .

Azeliragon was originally developed at TransTech Pharma. In September 2006, Pfizer entered into a license agreement with the company for the development and commercialization of small- and large-molecule compounds under development at TransTech. Pursuant to the collaboration, Pfizer gained exclusive worldwide rights to develop and commercialize TransTech’s portfolio of RAGE modulators, including azeliragon.

Reference：

1. WO03075921A2.

2. US2008249316A1.

US 20080249316

VTV Therapeutics

Azeliragon (TTP488) is an orally bioavailable small molecule that inhibits the receptor for advanced glycation endproducts (RAGE). A Phase 2 clinical trial to evaluate azeliragon as a potential treatment of mild-AD in patients with type 2 diabetes is ongoing. The randomized, double-blind, placebo-controlled multicenter trial is designed as sequential phase 2 and phase 3 studies operationally conducted under one protocol. For additional information on the study, refer to NCT03980730 at Clinicaltrials.gov.

RAGE is an immunoglobulin-like cell surface receptor that is overexpressed in brain tissues of patients with AD. The multiligand nature of RAGE is highlighted by its ability to bind diverse ligands such as advanced glycation end-products (AGEs), linked to diabetic complications and β-amyloid fibrils, a hallmark of AD. The association between type 2 diabetes and AD is well documented. A linear correlation between circulating hemoglobin A1c (HbA1c) levels and cognitive decline has been demonstrated in the English Longitudinal Study of Ageing.

PATENT

WO-2019190823

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019190823&tab=PCTDESCRIPTION&_cid=P12-K1K59I-21476-1

Novel crystalline forms of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine and its salt ( azeliragon ) (deignated as forms III and IV) as RAGE inhibitors useful for treating psoriasis, rheumatoid arthritis and Alzheimer’s disease.

The Receptor for Advanced Glycation Endproducts (RAGE) is a member of the immunoglobulin super family of cell surface molecules. Activation of RAGE in different tissues and organs leads to a number of pathophysiological consequences. RAGE has been implicated in a variety of conditions including: acute and chronic inflammation (Hofmann et al., Cell 97:889-901 (1999)), the development of diabetic late complications such as increased vascular permeability (Wautier et al., J. Clin. Invest. 97:238-243 (1995)), nephropathy (Teillet et al., J. Am. Soc. Nephrol. 11 : 1488- 1497 (2000)), atherosclerosis (Vlassara et. al., The Finnish Medical Society DUODECIM, Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al., Diabetologia 42:603-607 (1999)). RAGE has also been implicated in Alzheimer’s disease (Yan et al., Nature 382: 685-691 , (1996)), erectile dysfunction, and in tumor invasion and metastasis (Taguchi et al., Nature 405: 354-357, (2000)).

Binding of ligands such as advanced glycation endproducts (AGEs), S100/calgranulin/EN-RAGE, b-amyloid, CML (N^e-Carboxymethyl lysine), and amphoterin to RAGE has been shown to modify expression of a variety of genes. For example, in many cell types interaction between RAGE and its ligands generates oxidative stress, which thereby results in activation of the free radical sensitive transcription factor NF-kB, and the activation of NF-kB regulated genes, such as the cytokines IL- 1 b, TNF- a, and the like. In addition, several other regulatory pathways, such as those involving p21 ras.

MAP kinases, ERK1 and ERK2, have been shown to be activated by binding of AGEs and other ligands to RAGE. In fact, transcription of RAGE itself is regulated at least in part by NF-kB. Thus, an ascending, and often detrimental, spiral is fueled by a positive feedback loop initiated by ligand binding. Antagonizing binding of physiological ligands to RAGE, therefore, is our target, for down-regulation of the pathophysiological changes brought about by excessive concentrations of AGEs and other ligands for RAGE.

Pharmaceutically acceptable salts of a given compound may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, melting point, crystal shape, compaction behavior, flow properties, and/or solid state stability. These differences affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Although U.S. Patent No. 7,884,219 discloses Form I and Form II of COMPOUND I as a free base, there is a need for additional drug forms that are useful for inhibiting RAGE activity in vitro and in vivo, and have properties suitable for large-scale manufacturing and formulation. Provided herein

PATENT

WO03075921

PATENT

WO2019190822

PATENT

WO2008123914

Publications

Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics

Presentations and Posters

///////////Azeliragon, psoriasis, rheumatoid arthritis, Alzheimer’s disease, TTP-488, PF-04494700, RAGE inhibitors, TransTech Pharma, PHASE 3, Dementia, Alzheimer’s type,

CCCCC1=NC(=CN1C2=CC=C(C=C2)OC3=CC=C(C=C3)Cl)C4=CC=C(C=C4)OCCCN(CC)CC

J-147

September 6, 2019 6:51 am / Leave a comment

ChemSpider 2D Image | N-(2,4-Dimethylphenyl)-2,2,2-trifluoro-N'-[(E)-(3-methoxyphenyl)methylene]acetohydrazide | C18H17F3N2O2

J-147

N-(2,4-Dimethylphenyl)-2,2,2-trifluoro-N’-[(E)-(3-methoxyphenyl)methylene]acetohydrazide

Molecular FormulaC₁₈H₁₇F₃N₂O₂
Average mass350.335 Da

2,2,2-trifluoroacetic acid-1-(2,4-dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide

Acetic acid, 2,2,2-trifluoro-, 1-(2,4-dimethylphenyl)-2-[(1E)-(3-methoxyphenyl)methylene]hydrazide

N-(2,4-Dimethylphenyl)-2,2,2-trifluoro-N’-[(E)-(3-methoxyphenyl)methylene]acetohydrazide

[1146963-51-0]

1-(2,4-dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide, 2,2,2-trifluoro-acetic acid

1146963-51-0 [RN] DOUBLE BOND GEOMETRY UNSPECIFIED

1807913-16-1 [RN] AS PER https://chem.nlm.nih.gov/chemidplus/sid/1807913161 E FORM

FDA UNII Z41H3C5BT9

Abrexa Pharmaceuticals, Dementia, Alzheimer’s type, PHASE1
Blanchette Rockefeller Neurosci Inst (Originator)
Salk Institute for Biological Studies (Originator)

Abrexa Pharmaceuticals is developing the oral curcumin derivative J-147 for the treatment of Alzheimer’s disease. A phase I clinical trial is under way in healthy young and older adults.

The Salk Institute for Biological Studies and Abrexa Pharmaceuticals are developing J-147, a curcumin derivative CNB-001 , and a 5-lipoxygenase inhibitor, for the oral treatment of Alzheimer’s disease (AD), aging and acute ischemic stroke; in January 2019, a phase I trial for AD was initiated.

J147 is an experimental drug with reported effects against both Alzheimer’s disease and ageing in mouse models of accelerated aging.^[1]^[2]^[3]^[4]

The approach that lead to development of the J147 drug was to screen candidate molecules for anti-aging effects, instead of targeting the amyloid plaques. It is contrary to most other approaches to developing drugs against Alzheimer’s disease that target the plaque deposits in the brain.^[5]

The J147 drug is also reported to address other biological aging factors, such as preventing the leakage of blood from microvessels in mice brains.^[5] The development of J147 follows the chemical pharmacological way, contrary to biological ways that exploit e.g. use of bacteriophages.^[6]^[7]

Enhanced neurogenic activity over J147 in human neural precursor cells has its derivative called CAD-31. CAD-31 is enhancing the use of free fatty acids for energy production by shifting of the metabolic profile of fatty acids toward the production of ketone bodies, a potent source of energy in the brain when glucose levels are low.^[8]

The target molecule is a protein called ATP synthase, which is found in the mitochondria.^[9]

Image result for J-147

PAPER

Organic & Biomolecular Chemistry (2015), 13(37), 9564-9569

https://pubs.rsc.org/en/content/articlelanding/2015/OB/C5OB01463H#!divAbstract

A series of novel J147 derivatives were synthesized, and their inhibitory activities against β-amyloid (Aβ) aggregation and toxicity were evaluated by using the oligomer-specific antibody assay, the thioflavin-T fluorescence assay, and a cell viability assay in the transformed SH-SY5Y cell culture. Among the synthesized J147 derivatives, 3j with a 2,2-dicyanovinyl substituent showed the most potent inhibitory activity against Aβ₄₂oligomerization (IC₅₀ = 17.3 μM) and Aβ₄₂ fibrillization (IC₅₀ = 10.5 μM), and disassembled the preformed Aβ₄₂ fibrils with an EC₅₀ of 10.2 μM. Finally, we confirmed that 3j is also effective at preventing neurotoxicity induced by Aβ₄₂-oligomers as well as Aβ₄₂-fibrils.

Graphical abstract: Dicyanovinyl-substituted J147 analogue inhibits oligomerization and fibrillation of β-amyloid peptides and protects neuronal cells from β-amyloid-induced cytotoxicity

http://www.rsc.org/suppdata/c5/ob/c5ob01463h/c5ob01463h1.pdf

Synthesis of (E)-N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N’-(3-methoxybenzylidene)- 32 acetohydrazide (3a). To a solution of 3-methoxybenzaldehyde (1a) (0.10 g, 0.7 mmol) in EtOH (10 33 mL) was added (2,4-dimethylphenyl)hydrazine hydrochloride (0.13 g, 0.7 mmol), and the resulting 34 mixture was stirred for 1 h at room temperature (RT). After the reaction, the mixture was concentrated 35 under reduced pressure to yield the corresponding benzylidenehydrazine, which was used for the next 36 step without further purification. The intermediate benzylidenehydrazine was dissolved in CH2Cl2, 37 and the resulting solution was treated with Et3N (0.3 mL, 2.2 mmol). Trifluoroacetic anhydride (0.1 38 mL, 1.1 mmol) was added to this solution in drops at 0 °C. After stirring for 1 h, the mixture was 39 concentrated under reduced pressure, and the residue was purified by column chromatography on 40 silica gel (8:1 = hexanes:ether) to yield 3a (0.12 g, 0.3 mmol, 47% yield) as a yellow solid:

1H NMR 41 (400 MHz, CDCl3) δ 7.29-7.24 (m, 4H), 7.20 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.04 (d, J 42 = 7.9 Hz, 1H), 6.94 (ddd, J = 8.1, 2.2,0.8 Hz, 1H), 3.81 (s, 1H), 2.41 (s, 3H), 2.08 (s, 3H);

13C NMR 43 (100 MHz, CDCl3) δ 160.7, 158.9 (q, J = 36.4 Hz), 155.0, 143.4, 143.1, 142.3, 137.7, 134.4, 130.9, 44 130.8, 130.6, 129.9, 123.5, 123.0, 118.4 (q, J = 287.3 Hz), 113.8, 57.4, 23.5, 19.1;

LC-MS (ESI) m/z found 373.2 [M + Na]+ , calcd for C18H17F3N2O2Na 373.1.

PAPER

https://www.sciencedirect.com/science/article/pii/S0960894X12014746

Figure 1. Chemical structures of previously developed [¹¹C]PIB, [¹⁸F]Amyvid and [¹⁸F]-T808, and newly developed [¹¹C]J147.

Scheme 1. Synthesis of the reference standard J147 (2).

PRODUCT PATENT

WO2009052116

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009052116&tab=PCTDESCRIPTION

PATENT

WO-2019164997

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019164997&tab=PCTDESCRIPTION&_cid=P20-K07KTW-29673-1

A process for preparing crystalline Form II of 2,2,2-trifluoroacetic acid-1-(2,4-dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide (J-147; 98% of purity) comprising the steps of providing a slurry containing saturated amorphous or crystalline Form I of J-147 and mixing the slurry to obtain the crystalline Form II of J147. Also claimed are processes for preparing the crystalline Form I of 2,2,2-trifluoroacetic acid-1-(2,4-dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide. Further claimed are isolation of the crystalline Form II and I of 2,2,2-trifluoroacetic acid-1-(2,4-dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide. The compound is disclosed to be a neurotrophic agent and known to be a Trkb receptor agonist, useful for treating neurodegenerative disease, such as aging and motor neurone disease.

The present disclosure relates to polymorph forms of a pharmaceutical active agent. In particular, the present disclosure relates to polymorph forms of neuroprotective agent 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene] hydrazide (J147).

[0002] 2,2,2 -trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene] hydrazide (J147) is a potent orally active neurotrophic agent discovered during screening for efficacy in cellular models of age-associated pathologies and has a structure given by Formula I:

[0003] J147 is broadly neuroprotective, and exhibited activity in assays indicating distinct neurotoxicity pathways related to aging and neurodegenerative diseases, with EC50 between 10 and 200 nM. It has been indicated to improve memory in normal rodents, and prevent the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.

Furthermore, it has displayed neuroprotective, neuroanti-inflammatory, and LTP-enhancing activity.

[0004] The neurotrophic and nootropic effects have been associated with increases in BDNF levels and BDNF responsive proteins. Interestingly, despite this mechanism of action, Jl47’s neuroprotective effects have been observed to be independent of TrkB receptor activation.

J147 has been indicated to reduce soluble Ab40 and Ab42 levels, and it is currently being researched for potential applications in treating ALS.

The Fourier transform infrared (FTIR) spectrum is shown in Figure 4. Based on visual inspection the spectrum is consistent with structure. The Raman spectrum is in agreement with the FTIR spectrum and is shown in Figure 5. The proton NMR data is consistent with the structure of J147 and is shown in Figure 6. The proton NMR data is also shown in tabulated form in Table B below.

Table B

EXAMPLE OF PREPARATION OF FORM II OF J 147

Batch Process: About 100 kg of crude J147 from its synthetic preparation was evaporated twice from about 80 kg of ethanol. The crude product was taken up in about 48 kg of ethanol and the batch temperature was adjusted to 28 °C. About 37 kg of water was added gradually to the batch. The batch was held at about 30 °C for about 1.7 hours. A sample of the batch was pulled from the reactor and solids precipitated by addition of 45 mL of water. The solids obtained were added back to the batch as seed crystals and the mixture stirred for 40 minutes at 30 °C. An additional about 34 kg of water was added. The batch was held at about 18 °C for about 58 hours and then cooled to about 10 °C for another about 5.5 hours. Analysis of the resultant solids indicated the presence of Form I. Form I was converted to Form II by heating the slurry to about 45 °C for about 16 hours and then cooling back to about 10 °C and holding the batch at this temperature for about 3 hours about 17.7 kg of solid Form II of J147 were recovered by filtration after washing and drying.

CLIP

https://cen.acs.org/articles/90/i31/Tumeric-Derived-Compound-Curcumin-Treat.html

Turmeric-Derived Compound Curcumin May Treat Alzheimer’s

Curry chemical shows promise for treating the memory-robbing disease

By Lauren K. Wolf

Tumeric roots sit on a pile of powered turmeric, both are an intense, warm yellow.

CURRY WONDER

Curcumin, derived from the rootstalk of the turmeric plant, not only gives Indian dishes their color but might treat Alzheimer’s.

Credit: Shutterstock

More than 5 million people in the U.S. currently live with Alzheimer’s disease. And according to the Alzheimer’s Association, the situation is only going to get worse.

By 2050, the nonprofit estimates, up to 16 million Americans will have the memory-robbing disease. It will cost the U.S. $1.1 trillion annually to care for them unless a successful therapy is found.

Pharmaceutical companies have invested heavily in developing Alzheimer’s drugs, many of which target amyloid-β, a peptide that misfolds and clumps in the brains of patients. But so far, no amyloid-β-targeted medications have been successful. Expectation for the most advanced drugs—bapineuzumab from Pfizer and Johnson & Johnson and solanezumab from Eli Lilly & Co.—are low on the basis of lackluster data from midstage clinical trials. That sentiment was reinforced last week when bapineuzumab was reported to have failed the first of four Phase III studies.

Even if these late-stage hopefuls do somehow work, they won’t come cheap, says Gregory M. Cole, a neuroscientist at the University of California, Los Angeles. These drugs “would cost patients tens of thousands of dollars per year,” he estimates. That hefty price tag stems from bapineuzumab and solanezumab being costly-to-manufacture monoclonal antibodies against amyloid-β.

“There’s a great need for inexpensive Alzheimer’s treatments,” as well as a backup plan if pharma fails, says Larry W. Baum, a professor in the School of Pharmacy at the Chinese University of Hong Kong. As a result, he says, a great many researchers have turned their attention to less pricy alternatives, such as compounds from plants and other natural sources.

Curcumin, a spice compound derived from the rootstalk of the turmeric plant (Curcuma longa), has stood out among some of the more promising naturally derived candidates.

When administered to mice that develop Alzheimer’s symptoms, curcumin decreases inflammation and reactive oxygen species in the rodents’ brains, researchers have found. The compound also inhibits the aggregation of troublesome amyloid-β strands among the animals’ nerve cells. But the development of curcumin as an Alzheimer’s drug has been stymied, scientists say, both by its low uptake in the body and a lack of funds for effective clinical trials—obstacles researchers are now trying to overcome.

In addition to contributing to curry dishes’ yellow color and pungent flavor, curcumin has been a medicine in India for thousands of years. Doctors practicing traditional Hindu medicine admire turmeric’s active ingredient for its anti-inflammatory properties and have used it to treat patients for ailments including digestive disorders and joint pain.

Only in the 1970s did Western researchers catch up with Eastern practices and confirm curcumin’s anti-inflammatory properties in the laboratory. Scientists also eventually determined that the polyphenolic compound is an antioxidant and has chemotherapeutic activity.

Molecular structures of Curcumin and J147.

Bharat B. Aggarwal, a professor at the University of Texas M. D. Anderson Cancer Center, says curcumin is an example of a pleiotropic agent: It has a number of different effects and interacts with many targets and biochemical pathways in the body. He and his group have discovered that one important molecule targeted and subsequently suppressed by curcumin is NF-κB, a transcription factor that switches on the body’s inflammatory response when activated (J. Biol. Chem.,DOI: 10.1074/jbc.270.42.24995).

Aside from NF-κB, curcumin seems to interact with several other molecules in the inflammatory pathway, a biological activity that Aggarwal thinks is advantageous. “All chronic diseases are caused by dysregulation of multiple targets,” he says. “Chemists don’t yet know how to design a drug that hits multiple targets.” With curcumin, “Mother Nature has already provided a compound that does so.”

Curcumin’s pleiotropy also brought it to the attention of UCLA’s Cole during the early 1990s while he was searching for possible Alzheimer’s therapeutics. “That was before we knew about amyloid-β” and its full role in Alzheimer’s, he says. “We were working on the disease from an oxidative damage and inflammation point of view—two processes implicated in aging.”

When Cole and his wife, Sally A. Frautschy, also at UCLA, searched the literature for compounds that could tackle both of these age-related processes, curcumin jumped out at them. It also didn’t hurt that the incidence of Alzheimer’s in India, where large amounts of curcumin are consumed regularly, is lower than in other parts of the developing world (Lancet Neurol., DOI: 10.1016/s1474-4422(08)70169-8).

In 2001, Cole, Frautschy, and colleagues published the first papers that demonstrated curcumin’s potential to treat neurodegenerative disease (Neurobiol. Aging, DOI: 10.1016/s0197-4580(01)00300-1; J. Neurosci.2001, 8370). The researchers studied the effects of curcumin on rats that had amyloid-β injected into their brains, as well as mice engineered to develop amyloid brain plaques. In both cases, curcumin suppressed oxidative tissue damage and reduced amyloid-β deposits.

Those results, Cole says, “turned us into curcumin-ologists.”

Although the UCLA team observed that curcumin decreased amyloid plaques in animal models, at the time, the researchers weren’t sure of the molecular mechanism involved.

Soon after the team’s first results were published, Cole recalls, a colleague brought to his attention the structural similarity between curcumin and the dyes used to stain amyloid plaques in diseased brain tissue. When Cole and Frautschy tested the spice compound, they saw that it, too, could stick to aggregated amyloid-β. “We thought, ‘Wow, not only is curcumin an antioxidant and an anti-inflammatory, but it also might be an anti-amyloid drug,’ ” he says.

In 2004, a group in Japan demonstrated that submicromolar concentrations of curcumin in solution could inhibit aggregation of amyloid-β and break up preformed fibrils of the stuff (J. Neurosci. Res., DOI: 10.1002/jnr.20025). Shortly after that, the UCLA team demonstrated the same (J. Biol. Chem., DOI: 10.1074/jbc.m404751200).

As an Alzheimer’s drug, however, it’s unclear how important it is that the spice compound inhibits amyloid-β aggregation, Cole says. “When you have something that’s so pleiotropic,” he adds, “it’s hard to know” which of its modes of action is most effective.

Having multiple targets may be what helps curcumin have such beneficial, neuroprotective effects, says David R. Schubert, a neurobiologist at the Salk Institute for Biological Studies, in La Jolla, Calif. But its pleiotropy can also be a detriment, he contends.

The pharmaceutical world, Schubert says, focuses on designing drugs aimed at hitting single-target molecules with high affinity. “But we don’t really know what ‘the’ target for curcumin is,” he says, “and we get knocked for it on grant requests.”

Another problem with curcumin is poor bioavailability. When ingested, UCLA’s Cole says, the compound gets converted into other molecular forms, such as curcumin glucuronide or curcumin sulfate. It also gets hydrolyzed at the alkaline and neutral pHs present in many areas of the body. Not much of the curcumin gets into the bloodstream, let alone past the blood-brain barrier, in its pure, active form, he adds.

Unfortunately, neither Cole nor Baum at the Chinese University of Hong Kong realized the poor bioavailability until they had each launched a clinical trial of curcumin. So the studies showed no significant difference between Alzheimer’s patients taking the spice compound and those taking a placebo (J. Clin. Psychopharmacol., DOI: 10.1097/jcp.0b013e318160862c).

“But we did show curcumin was safe for patients,” Baum says, finding a silver lining to the blunder. “We didn’t see any adverse effects even at high doses.”

Some researchers, such as Salk’s Schubert, are tackling curcumin’s low bioavailability by modifying the compound to improve its properties. Schubert and his group have come up with a molecule, called J147, that’s a hybrid of curcumin and cyclohexyl-bisphenol A. Like Cole and coworkers, they also came upon the compound not by initially screening for the ability to interact with amyloid-β, but by screening for the ability to alleviate age-related symptoms.

The researchers hit upon J147 by exposing cultured Alzheimer’s nerve cells to a library of compounds and then measuring changes to levels of biomarkers for oxidative stress, inflammation, and nerve growth. J147 performed well in all categories. And when given to mice engineered to accumulate amyloid-β clumps in their brains, the hybrid molecule prevented memory loss and reduced formation of amyloid plaques over time (PLoS One, DOI: 10.1371/journal.pone.0027865).

Other researchers have tackled curcumin’s poor bioavailability by reformulating it. Both Baum and Cole have encapsulated curcumin in nanospheres coated with either polymers or lipids to protect the compound from modification after ingestion. Cole tells C&EN that by packaging the curcumin in this way, he and his group have gotten micromolar quantities of it into the bloodstream of humans. The researchers are now preparing for a small clinical trial to test the formulation on patients with mild cognitive impairment, who are at an increased risk of developing Alzheimer’s.

An early-intervention human study such as this one comes with its own set of challenges, Cole says. People with mild cognitive impairment “have good days and bad days,” he says. A large trial over a long period would be the best way to get any meaningful data, he adds.

Such a trial can cost up to $100 million, a budget big pharma might be able to scrape together but that is far out of reach for academics funded by grants, Cole says. “If you’re down at the level of what an individual investigator can do, you’re running a small trial,” he says, “and even if the result is positive, it might be inconclusive” because of its small size or short duration. That’s one of the reasons the curcumin work is slow-going, Cole contends.

The lack of hard clinical evidence isn’t stopping people from trying curcumin anyway. Various companies are selling the spice compound as a dietary supplement, both in its powdered form and in nanoformulations such as the ones Cole and Baum are working with. Indiana-based Verdure Sciences, for instance, licensed a curcumin nanoformulation from UCLA and sells it under the name Longvida (about $1.00 to $2.00 per capsule, depending on the distributor).

“There’s no proof that it works,” Cole says. “If you want to take it, you’re experimenting on yourself.” And he cautions that correct dosing for this more bioavailable form of curcumin hasn’t yet been established, so there could be safety concerns.

But on the basis of positive e-mails he’s received from caregivers and Alzheimer’s patients who are desperate for options and trying supplements, “I have some hope,” Cole says. “Maybe there’s something to curcumin after all.”

CLIP

J 147 powder

Raw J 147 powder basic Characters

Name:	J 147 powder
CAS:	1146963-51-0
Molecular Formula:	C18H17F3N2O2
Molecular Weight:	350.3349896
Melt Point:	177-178°C
Storage Temp:	4°C
Color:	White or off white powder

Raw J 147 powder in enhance brain function and an extra boost cycle

Names

J 147 powder

J 147 (1146963-51-0) Usage dosage

Using a drug discovery scheme for Alzheimer’s disease (AD) that is based upon multiple pathologies of old age, we identified a potent compound with efficacy in rodent memory and AD animal models. Since this compound, J-147 powder, is a phenyl hydrazide, there was concern that it can be metabolized to aromatic amines/hydrazines that are potentially carcinogenic. To explore this possibility, we examined the metabolites of J 147 powder in human and mouse microsomes and mouse plasma. It is shown that J-147(1146963-51-0) powder is not metabolized to aromatic amines or hydrazines, that the scaffold is exceptionally stable, and that the oxidative metabolites are also neuroprotective. It is concluded that the major metabolites of J 147(1146963-51-0) powder may contribute to its biological activity in animals.
J 147 , derived from the curry spice component curcumin, has low toxicity and actually reverses damage in neurons associated with Alzheimer’s.

J 147 (1146963-51-0) was the mitochondrial protein known as ATP synthase, specifically ATP5A, a subunit of that protein. ATP synthase is involved in the mitochondrial generation of ATP, which cells use for energy.

The researchers demonstrated that by reducing the activity of ATP synthase, they were able to protect neuronal cells from a number of toxicities associated with the aging of the brain. One reason for this neuroprotective effect is thought to be the role of excitotoxicity in neuronal cell damage.

Excitotoxicity is the pathological process by which neurons are damaged and killed by the overactivation of receptors for the excitatory neurotransmitter glutamate. Think of it being a bit like a light switch being turned on and off so rapidly that it ends up causing the light bulb to blow.

Recently, the role of ATP synthase inhibition for neuroprotection against excitotoxic damage was demonstrated in a mouse study[4]. The second study showed that mouse models expressing the human form of mutant ATPase inhibitory factor 1 (hIF1), which causes a sustained inhibition of ATP synthase, were more resilient to neuronal death after excitotoxic damage. This data is consistent with this new J 147 powder study, in which an increase in IF1 in the mice reduced the activity of ATP synthase (specifically ATP5A) and was neuroprotective.

Warning on Raw J 147 powder

Data presented here demonstrate that J-147 powder has the ability to rescue cognitive deficits when administered at a late stage in the disease. The ability of J-147 powder to improve memory in aged AD mice is correlated with its induction of the neurotrophic factors NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor) as well as several BDNF-responsive proteins which are important for learning and memory. The comparison between J-147(1146963-51-0) powder and donepezil in the scopolamine model showed that while both compounds were comparable at rescuing short term memory, J-147 powder was superior at rescuing spatial memory and a combination of the two worked best for contextual and cued memory.

Further instructions

Alzheimer’s disease is a progressive brain disorder, recently ranked as the third leading cause of death in the United States and affecting more than five million Americans. It is also the most common cause of dementia in older adults, according to the National Institutes of Health. While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), few have proven effective in the clinic.

“While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), none have proven effective in the clinic,” says Schubert, senior author of the study.

Several years ago, Schubert and his colleagues began to approach the treatment of the disease from a new angle. Rather than target amyloid, the lab decided to zero in on the major risk factor for the disease–old age. Using cell-based screens against old age-associated brain toxicities, they synthesized J 147(1146963-51-0) powder.

Previously, the team found that J-147 powder could prevent and even reverse memory loss and Alzheimer’s pathology in mice that have a version of the inherited form of Alzheimer’s, the most commonly used mouse model. However, this form of the disease comprises only about 1 percent of Alzheimer’s cases. For everyone else, old age is the primary risk factor, says Schubert. The team wanted to explore the effects of the drug candidate on a breed of mice that age rapidly and experience a version of dementia that more closely resembles the age-related human disorder.

Raw J-147 powder (1146963-51-0) hplcâ¥98% | AASraw SARMS powder

References

^ “Experimental drug targeting Alzheimer’s disease shows anti-aging effects” (Press release). Salk Institute. 12 November 2015. Retrieved November 13, 2015.
^ Chen Q, Prior M, Dargusch R, Roberts A, Riek R, Eichmann C, Chiruta C, Akaishi T, Abe K, Maher P, Schubert D (14 December 2011). “A novel neurotrophic drug for cognitive enhancement and Alzheimer’s disease”. PLoS One. 6 (12): e27865. doi:10.1371/journal.pone.0027865. PMC 3237323. PMID 22194796.
^ Currais A, Goldberg J, Farrokhi C, Chang M, Prior M, Dargusch R, Daugherty D, Armando A, Quehenberger O, Maher P, Schubert D (11 November 2015). “A comprehensive multiomics approach toward understanding the relationship between aging and dementia” (PDF). Aging. 7 (11): 937–55. doi:10.18632/aging.100838. PMC 4694064. PMID 26564964.
^ Prior M, Dargusch R, Ehren JL, Chiruta C, Schubert D (May 2013). “The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer’s disease mice”. Alzheimer’s Research & Therapy. 5 (3): 25. doi:10.1186/alzrt179. PMC 3706879. PMID 23673233.
^ Jump up to:^a ^b Brian L. Wang (13 November 2015). “Experimental drug targeting Alzheimer’s disease shows anti-aging effects in animal tests”. nextbigfuture.com. Retrieved November 16, 2015.
^ Krishnan R, Tsubery H, Proschitsky MY, Asp E, Lulu M, Gilead S, Gartner M, Waltho JP, Davis PJ, Hounslow AM, Kirschner DA, Inouye H, Myszka DG, Wright J, Solomon B, Fisher RA (2014). “A bacteriophage capsid protein provides a general amyloid interaction motif (GAIM) that binds and remodels misfolded protein assemblies”. Journal of Molecular Biology. 426: 2500–19. doi:10.1016/j.jmb.2014.04.015. PMID 24768993.
^ Solomon B (October 2008). “Filamentous bacteriophage as a novel therapeutic tool for Alzheimer’s disease treatment”. Journal of Alzheimer’s Disease. 15 (2): 193–8. PMID 18953108.
^ Daugherty, D., Goldberg, J., Fischer, W., Dargusch, R., Maher, P., & Schubert, D. (2017). A novel Alzheimer’s disease drug candidate targeting inflammation and fatty acid metabolism. Alzheimer’s research & therapy, 9(1), 50. https://doi.org/10.1186/s13195-017-0277-3
^ “Researchers identify the molecular target of J147, which is nearing clinical trials to treat Alzheimer’s disease”. Retrieved 2018-01-30.

J147
Legal status

Legal status	US: Investigational New Drug
Identifiers
IUPAC name [show]
CAS Number	1146963-51-0
PubChem CID	25229652
ChemSpider	29341612
Chemical and physical data
Formula	C₁₈H₁₇F₃N₂O₂
Molar mass	350.341 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] CC1=C(C=CC(=C1)C)N(C(C(F)(F)F)=O)\N=C\C2=CC(=CC=C2)OC
InChI [hide] InChI=1S/C18H17F3N2O2/c1-12-7-8-16(13(2)9-12)23(17(24)18(19,20)21)22-11-14-5-4-6-15(10-14)25-3/h4-11H,1-3H3/b22-11+ Key:HYMZAYGFKNNHDN-SSDVNMTOSA-N

////////////J-147, J 147, J147, Alzheimer’s disease, neurotrophic agent, The Salk Institute for Biological Studies, Abrexa Pharmaceuticals, PHASE 1, CURCUMIN

CAS 1417911-00-2

Acetic acid, 2,2,2-trifluoro-, 1-(2,4-dimethylphenyl)-2-[[3-(methoxy-¹¹C)phenyl]methylene]hydrazide

CT 1812

May 18, 2019 3:35 am / 1 Comment on CT 1812

CT-1812

Elayta

Condition(s): Alzheimer’s Disease
U.S. FDA Status: Alzheimer’s Disease (Phase 2)
Company: Cognition Therapeutics Inc.

CAS: 1802632-22-9
Chemical Formula: C24H33NO4S
Molecular Weight: 431.591

2-(tert-butoxy)-4-(3-methyl-3-(5-(methylsulfonyl)isoindolin-2-yl)butyl)phenol

Phenol, 4-[3-[1,3-dihydro-5-(methylsulfonyl)-2H-isoindol-2-yl]-3-methylbutyl]-2-(1,1-dimethylethoxy)-

Originator Cognition Therapeutics
Class Antidementias; Neuroprotectants; Nootropics; Small molecules
Mechanism of Action Sigma-2 receptor antagonists

Phase II Alzheimer’s disease
Phase I Cognition disorders

21 Feb 2019 Cognition Therapeutics receives patent for a composition of matter patent covering Elayta™ in Europe
19 Feb 2019 Pharmacokinetics and adverse events data from a phase I trial in Cognition disorders released by Cognition Therapeutics
22 Oct 2018 CTP push 289675: Updated KDM, forwarded USA line from PI/II to PII

CT-1812 is a first-in-class, orally available sigma-2/PGRMC1 antagonist (alpha beta oligomer receptor antagonist), is being developed by Cognition. sCT-1812 is a novel therapeutic candidate for Alzheimer’s disease

SYN

BACKGROUND

CT1812 is a small-molecule antagonist of the sigma2 receptor, also known as the progesterone receptor membrane component 1. The rationale behind this therapeutic approach is that ligands for the sigma2/PGRMC1 receptor will compete with oligomeric Aβ binding to this receptor and thus interfere with Aβ-induced synaptic toxicity. CT1812 grew out of screening programs at Cognition Therapeutics. Company scientists have reported that compounds in this series not only block binding of a range of different Aβ species to this receptor but also displace it when applied after Aβ has bound (Dec 2014 conference news).

The structure of CT1812 has not been disclosed, but similar compounds in the series have been reported to enter the brain, occupy up to 80 percent of sigma2/PGRMC1 receptors, and restore behavioral deficits in APP transgenic mice (Izzo et al., 2014; Izzo et al., 2014).

FINDINGS

From September 2015 to May 2016, Cognition Therapeutics ran a Phase 1 trial in 80 healthy volunteers aged 18 to 75 in Melbourne, Australia; target enrollment was originally listed as 114. Single-ascending-dose administration was followed by multiple ascending doses given once daily for two weeks. The dose range in this trial spanned 10 to 650 mg; if this would not generate data to set a maximum tolerated dose, doses up to 1,350 mg were to be tried. Outcome measures included safety, tolerability, plasma pharmacokinetics, and CSF CT1812 concentration. At the 2016 and 2017 AAIC conferences, company scientists reported that single doses up to 1,120 mg were given, as were multiple doses of up to 840 mg in young and up to 560 mg in elderly volunteers. The drug was reported to be well-tolerated, with suitable pharmacokinetics, sufficient brain penetrance and target exposure, and minimal drug-drug interactions affecting cytochrome P450 activity (Catalano et al., 2016; Catalano et al., 2017).

From September 2016 to August 2017, Cognition Therapeutics ran a Phase 1/2 trial at four sites in Australia, enrolling 19 participants with mild to moderate Alzheimer’s disease supported by a recent MRI. It compared a four-week course of 90, 280, or 560 mg of CT 1812 to placebo, taken once daily, on safety and tolerability parameters. At the subsequent CTAD conference, Elayta was reported to have been generally safe and well tolerated, though there were four cases of lymphocytopenia. Exploratory measures such as ADAS-Cog14, verbal or category fluency tests recorded no difference between groups, but exploratory biomarker analyses yielded possible signals of synapse protection (Dec 2017 conference news).

In April 2018, a Phase 1/2 study started enrolling 21 people whose mild to moderate AD was confirmed by amyloid PET or CSF testing. Conducted at Yale University School of Medicine and dubbed COG0105 or SPARC, this trial will compare a six-month course of 100 or 300 mg of Elayta, or placebo. The primary outcome is cognition as assessed by the Alzheimer’s Disease Clinical Study Activities of Daily Living (ADCS-ADL), but the trial will also use the investigational PET tracer UCB-J, which binds to the synaptic vesicle glycoprotein 2A, in an attempt to monitor synapse density before and after treatment (see company press release; Jul 2016 news).

In summer 2018, a Phase 1b target engagement study at the University of Pennsylvania will start enrolling 18 people whose mild to moderate AD is confirmed by amyloid PET. Called COG0104 or SNAP, it will compare single injections of 90, 280, or 560 mg of Elayta or placebo for their ability to displace Aβ oligomers and clear them into the CSF, as measured by a CSF Aβ oligomer assay.

Also in summer 2018, a Phase 2 multi-center study is expected to begin enrolling 24 people with mild to moderate AD as confirmed by amyloid PET for a six-month course of 100 or 300 mg of Elayta, or placebo. As of May 22, 2018, this trial lists CT1812 pharmacodynamic effects on CSF biomarkers, specifically as assessed by CSF neurogranin levels, as primary outcome.

For all trials of this compound, see clinicaltrials.gov.

PATENT

WO 2015116923

https://patents.google.com/patent/WO2015116923A1

There are only five medications currently FDA-approved for the treatment of Alzheimer’s Disease (AD). Four are cholinesterase inhibitors: tacrine (COGNEX®; Sciele), donepezil (ARICEPT®; Pfizer), rivastigmine (EXELON®; Novartis), and galantamine (RAZADYNE®; Ortho-McNeil-Janssen). Donepezil, rivastigmine, and galantamine are successors to tacrine, a first generation compound rarely prescribed because of the potential for hepatotoxicity; they are roughly equally efficacious at providing symptomatic improvement of cognition and function at all stages of AD. The fifth approved medication is memantine (NAMENDA®; Forest), a low-affinity, use dependent N-methyl-D-aspartate glutamate receptor antagonist that offers similar benefits, but only in moderate to severe AD. The clinical effects of these compounds are small and impermanent, and currently available data are inconclusive to support their use as disease modifying agents. See, e.g., Kerchner et al, 2010, Bapineuzumab, Expert Opin Biol Ther., 10(7): 1121-1130. Clearly, alternative approaches to treatment of AD are required.

[004] Certain isoindoline compounds are provided that act as sigma-2 receptor functional antagonists and inhibit the deleterious effects of soluble Αβ oligomers. In some embodiments, isoindoline sigma-2 receptor antagonist compounds and compositions are used to treat or prevent synaptic dysfunction in a subject.

Example 21 illustrates representative preparation of 2-(Tert-butoxy)-

4-(3-methyl-3-(5-(methylsulfonyl)isoindolin-2-yl)butyl)phenol, Example Compound 62, as shown in Scheme 17.

10 Compound 62

[0534] Scheme 17: Procedure for preparation of 2-(Tert-butoxy)-4-(3- methyl-3-(5-(methylsulfonyl)isoindolin-2-yl)butyl)phenol, Example Compound 62.

[0535] Preparation of compound l(Scheme 17): To a glass pressure -bottle at -30 °C containing a mixture of catechol (50.0 g, 454 mmol, 1.0 eq), concentrated sulfuric acid (0.3 mL) in dichloromethane (200 mL), isobutene (152.6 g, 2.72 mol, 6.0 eq) was condensed. After sealing the pressure-bottle with a threaded Teflon cap tipped with a Teflon-protected rubber O-ring, the mixture was heated at 35 °C for 3 h until a clear solution was obtained. After cooling (-30 °C), triethylamine (1.5 mL, 10.8 mmol) was added and the mixture was concentrated. The residue was suspended in 0.5 M NaOH (1 L) and stirred for 10 min. The dark-green colored solution was washed with petroleum ether (2x 100 mL) and the washing layers were reextracted with 0.5 M NaOH (3x 100 mL). The combined aqueous layers were brought to pH 7-8 with 2 N HCl (400 mL), and extracted with ethyl acetate (2* 1 L), dried over sodium sulfate and concentrated to afford product 1 (67.7 g, 90%) as a colorless oil, which was used directly for the next step reaction without further purification. TLC: PE/EA = 50/1 ; R_f (Catechol) = 0.1 ; R_f (Compound 1) = 0.6.

[0536] Preparation of compound 2 (Scheme 17): To a stirred solution of compound 1 (1 12.2 g, 676 mmol, 1.2 eq) and potassium iodide (1 12.2 g, 676 mmol, 1.0 eq) in methanol (2 L) at 0 °C was slowly added sodium hydroxide (27.0 g, 676 mmol, 1.0 eq), followed with aqueous sodium chlorite (7% aq., 718.8 mL, 710 mmol, 1.05 eq) dropwise over 3 h while keeping the reaction below 0 °C. The mixture was stirred at 0 °C for another 30 min and neutralized by adding 2 N HCl at 0 °C till pH 7, extracted with DCM (2 x 1 L). The organic layers were dried over sodium sulfate and concentrated to afford product 2 (179.8 g, 91%). TLC: PE/EA = 50/1; R_f(Compound 1) = 0.6 ; R_f (Compound 2) = 0.6.

[0537] Preparation of compound 3(Scheme 17): To a stirred solution of compound 2 (179.8 g, 616 mmol, 1.0 eq) and triethylamine (186.6 g, 1.85 mol, 3.0 eq) in dichloromethane (2 L) at 0 °C was slowly added acetyl chloride (53.2 g, 677 mmol, 1.1 eq). The mixture was stirred at 0 °C for another 30 min, and warmed up to rt, and stirred at rt for 3 h, water (1 L) was added into the reaction mixture and the organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 3 (206 g, 100%), which was used directly to the next step without further purification. TLC: PE/EA = 50/1; R_f (Compound 2) = 0.6; R_f (Compound 3) = 0.5.

[0538] Preparation of compound 4 (Scheme 17): To a stirred solution of compound 3 (206 g, 616 mmol, 1.0 eq) in triethylamine (4.0 L) was added 2- methylbut-3-yn-2-amine (102.5 g, 1.23 mol, 2.0 eq), Pd(PPh₃)₂Cl₂ (15.1 g, 18.5 mmol, 0.03 eq) and copper(I) iodide (5.9 g, 31 mmol, 0.05 eq) and resulting mixture was stirred at rt for 17 h. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography to afford the title compound 4 (132.7 g, 74%). TLC: PE/EA = 1/1; R_f (Compound 3) = 0.9; R_f (Compound 4) = 0.3. [0539] Preparation of compound 5(Scheme 17): To a stirred solution of compound 4 (104.5 g, 0.36 mol) in ethanol (1.5 L) was added Pd/C (10% wt, 10.5 g). The mixture was stirred under hydrogen (balloon) overnight, and filtered. The filtrate was evaporated to dryness to afford compound 5 (106.3 g, 100%), which was used directly to the next step without further purification. TLC: PE/EA = 1/1; R_f(Compound 4) = 0.3 ; R_f (Compound 5) = 0.3.

[0540] Preparation of compound 6 (Scheme 17): To a solution of o-xylene

(115.7 g, 1.09 mol, 1.0 eq) in chloroform (1.0 L) at 0 °C was added C1S0₃H (254 g, 2.18 mol, 2.0 eq) dropwise. After the addition, the reaction mixture was stirred at room temperature for 2 days, and poured into ice. The crude mixture was extracted with dichloromethane (3 x 1.0 L). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to afford the crude compound 6 (161.5 g, 80%) as a white solid, which was used directly to the next step without further purification. TLC: PE/EA = 5/1; R_f (Compound 6) = 0.7.

[0541] General procedure for the preparation of compound 7 (Scheme

17): To a stirred solution of compound 6 (161.5 g, 0.87 mol, 1.0 eq) in saturated sodium sulfite solution (273 g, 2.17 mol, 2.5 eq, in 2.0 L of water) was added dropwise 32% NaOH (69.4 g, 1.73 mol, 2.0 eq) till the solution reached pH 9. After stirring at rt overnight, the reaction mixture was acidified with cone. HC1 in ice- cooling bath till pH 1. The precipitate was filtered, and washed with ice-water (2x), dried in vacuo to afford the crude product 7 (131 g, 88%), which was used directly for next step without further purification. TLC: PE/EA = 5/1; R_f (Compound 6) = 0.7; R_f (Compound 7) = 0.6.

[0542] Preparation of compound 8 (Scheme 17): To a stirred solution of compound 7 (130 g, 0.76 mol, 1.0 eq) and potassium carbonate (211 g, 1.53 mol, 2.0 eq) in DMF (300 mL) was added iodomethane (96 mL, 1.53 mol, 2.0 eq). The reaction was stirred at 40 °C overnight. The reaction mixture was evaporated to dryness, extracted with ethyl acetate. The organic layers were washed with water and brine, dried over sodium sulfate and concentrated, purified by flash column chromatography (PE: EA,10: 1 ~ 5: 1) to afford compound 8 (85.2 g, 61%). TLC: PE/EA = 5/1; R_f (Compound 7) = 0.6; R_f (Compound 8) = 0.3. [0543] Preparation of compound 9 (Scheme 17):To a stirred solution of compound 8 (78.2 g, 424 mmol, 1.0 eq) in 1 ,2-dichloroethane (1.2 L), were added N-bromosuccinimide (166 g, 934 mmol, 2.2 eq) and AIBN (6.9 g, 42.4 mmol, 0.1 eq). The reaction was stirred at reflux overnight. The reaction was diluted with water and dichloromethane. The organic layer was collected, and dried over sodium sulfate and concentrated, purified by flash column chromatography to afford compound 9, which was further recrystallized from hot methanol to afford the pure product 8 (75 g, 52%). TLC: PE/EA = 5/1; R_f (Compound 8) = 0.3; R_f (Compound 9) = 0.2.

[0544] Preparation of compound 10 (Scheme 17):To a stirred solution of compound 5 (46 g, 157 mmol, 1.0 eq) and compound 9 (53.5 g, 157 mmol, 1.0 eq) in THF (460 mL) was added triethylamine (47.7 g, 472 mmol, 3.0 eq). The reaction was stirred at 40 °C overnight, filtered and the filtrate was evaporated to dryness and purified by flash column chromatography to afford compound 10 (45 g, 63%). TLC: PE/EA = 1/1; R_f (Compound 5) = 0.3; R_f (Compound 9) = 1.0; R_f (Compound 10) = 0.4.

[0545] Preparation of Compound 62 (Scheme 17):To a stirred solution of compound 10 (45 g, 98.4 mmol) in methanol (300 mL) was added sodium methoxide (844 mg, 15.6 mmol, 0.16 eq) in one portion. The solution was stirred at rt overnight. Water (250 mL) was added dropwise into the reaction mixture over 1 h, the mixture was stirred at rt for 2 h, and filtered. The white solid was collected and dried on vacuum overnight to afford pure example Compound 62 base (38 g, 89%>). TLC: PE/EA = 1/1; R_f (Compound 10) = 0.4; R_f (Compound 62) = 0.4; ESI-MS: 432 (M+l)⁺; 1H NMR (400 MHz, CDC1₃) δ 7.80-7.78 (m, 2H). 7.40-7.38 (m, 1H), 6.87-6.79 (m, 3H), 5.58 (s, 1H), 4.11 (s, 4H), 3.05 (s, 3H), 2.61-2.57 (m, 2H), 1.76- 1.72 (m, 2H), 1.48 (s, 9H), 1.18 (s, 6H). Example 22: Preparation of (2-(4-(4-Hydroxy-3-methoxyphenyl)-2- methylbutan-2-yl)isoindolin-4-yl)(piperazin-l-yl)methanone,

REFERENCES

1: Grundman M, Morgan R, Lickliter JD, Schneider LS, DeKosky S, Izzo NJ,
Guttendorf R, Higgin M, Pribyl J, Mozzoni K, Safferstein H, Catalano SM. A phase
1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a
novel therapeutic candidate for Alzheimer’s disease. Alzheimers Dement (N Y).
2019 Jan 23;5:20-26. doi: 10.1016/j.trci.2018.11.001. eCollection 2019. PubMed
PMID: 30723776; PubMed Central PMCID: PMC6352291.

Paper Citations

Catalano S, Grundman M, Schneider LS, DeKosky S, Morgan R, Higgin M, Pribyl J, Mozzoni K, Izzo NJ, Safferstein H, Lickliter J. A Two-Part, Double-Blind, Placebo-Controlled, Phase 1 Study of the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Ct1812 in Healthy Volunteers. Alzheimer’s & Dementia, July 2016, Volume 12, Issue 7, Supplement
Catalano S, Grundman M, Schneider LS, DeKosky S, Morgan R, Guttendorf R, Higgin M, Pribyl J, Mozzoni K, Izzo NJ, Safferstein H. A Phase 1 Safety Trial of the aβ Oligomer Receptor Antagonist CT1812. Alzheimer’s & Dementia, July 2017, Volume 13, Issue 7
Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd, Vaswani A, Wardius M, Syed Z, Ravenscroft J, Mozzoni K, Silky C, Rehak C, Yurko R, Finn P, Look G, Rishton G, Safferstein H, Miller M, Johanson C, Stopa E, Windisch M, Hutter-Paier B, Shamloo M, Arancio O, LeVine H 3rd, Catalano SM. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One. 2014;9(11):e111898. Epub 2014 Nov 12 PubMed.
Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, Rehak C, Yurko R, Look G, Rishton G, Safferstein H, Cruchaga C, Goate A, Cahill MA, Arancio O, Mach RH, Craven R, Head E, LeVine H 3rd, Spires-Jones TL, Catalano SM. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One. 2014;9(11):e111899. Epub 2014 Nov 12PubMed.

/////CT-1812, CT 1812, CT1812, Alzheimers , Cognition Therapeutics, Elayta, phase 2, Cognition disorders

OC1=CC=C(CCC(C)(N2CC3=C(C=C(S(=O)(C)=O)C=C3)C2)C)C=C1OC(C)(C)C

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J-147