Category: 128577-47-9

Kozikowski, Alan P.; Shen, Sida; Pardo, Marta; Tavares, Mauricio T.; Szarics, Dora; Benoy, Veronick; Zimprich, Chad A.; Kutil, Zsofia; Zhang, Guiping; Barinka, Cyril; Robers, Matthew B.; Van Den Bosch, Ludo; Eubanks, James H.; Jope, Richard S. published the artcile< Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome>, Computed Properties of 128577-47-9, the main research area is Phenylhydroxamate permeability Ames neg acetylated memory and learning impairments; Ames negative; Phenylhydroxamate; acetylated α-tubulin; memory and learning impairments; permeability.

Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacol. and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1-/- mice. This small mol. demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC50 = 2.3 nM), with at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms. Moreover, through its inhibition of the α-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates α-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated α-tubulin levels in the hippocampus of Fmr1-/- mice. Lastly, SW-100 ameliorates several memory and learning impairments in Fmr1-/- mice, thus modeling the intellectual deficiencies associated with FXS, and hence providing a strong rationale for pursuing HDAC6-based therapies for the treatment of this rare disease.

ACS Chemical Neuroscience published new progress about Blood-brain barrier. 128577-47-9 belongs to class bromides-buliding-blocks, and the molecular formula is C9H8BrFO2, Computed Properties of 128577-47-9.

Referemce:
Bromide – Wikipedia,
bromide – Wiktionary

Sander, Kerstin; Galante, Eva; Gendron, Thibault; Yiannaki, Elena; Patel, Niral; Kalber, Tammy L.; Badar, Adam; Robson, Mathew; Johnson, Sean P.; Bauer, Florian; Mairinger, Severin; Stanek, Johann; Wanek, Thomas; Kuntner, Claudia; Kottke, Tim; Weizel, Lilia; Dickens, David; Erlandsson, Kjell; Hutton, Brian F.; Lythgoe, Mark F.; Stark, Holger; Langer, Oliver; Koepp, Matthias; Arstad, Erik published the artcile< Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography>, SDS of cas: 128577-47-9, the main research area is fluorine 18 PET tracer imaging drug efflux transporter.

Increased activity of efflux transporters, e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), at the blood-brain barrier is a pathol. hallmark of many neurol. diseases, and the resulting multiple drug resistance represents a major clin. challenge. Noninvasive imaging of transporter activity can help to clarify the underlying mechanisms of drug resistance and facilitate diagnosis, patient stratification, and treatment monitoring. We have developed a metabolically activated radiotracer for functional imaging of P-gp/BCRP activity with positron emission tomog. (PET). In preclin. studies, the tracer showed excellent initial brain uptake and clean conversion to the desired metabolite, although at a sluggish rate. Blocking with P-gp/BCRP modulators led to increased levels of brain radioactivity; however, dynamic PET did not show differential clearance rates between treatment and control groups. Our results provide proof-of-concept for development of prodrug tracers for imaging of P-gp/BCRP function in vivo but also highlight some challenges associated with this strategy.

Journal of Medicinal Chemistry published new progress about ATP-binding cassette transporter ABCG2 Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 128577-47-9 belongs to class bromides-buliding-blocks, and the molecular formula is C9H8BrFO2, SDS of cas: 128577-47-9.

Referemce:
Bromide – Wikipedia,
bromide – Wiktionary

Rabal, Obdulia; Sanchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; de Miguel, Irene; Perez-Gonzalez, Marta; Garcia-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso de Mendoza, Ander; Saez, Elena; Espelosin, Maria; Ursua, Susana; Tan, Haizhong; Wu, Wei; Xu, Musheng; Garcia-Osta, Ana; Oyarzabal, Julen published the artcile< Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease>, Recommanded Product: Methyl 4-(bromomethyl)-3-fluorobenzoate, the main research area is phosphodiesterase PDE5 histone deacetylase HDAC6 inhibitor Alzheimer disease; Alzheimer; Dual inhibitors; HDAC6 selective; In-vivo test; PDE5 inhibition; Pharmacological tool compound; Tg2576 mice.

The authors have identified chem. probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference vs. class I HDACs) to decipher the contribution of HDAC isoforms to the pos. impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer’s disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class mols. with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b (5-[[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl]methyl]thiophene-2-carbohydroxamic acid), which fulfilled the biochem., functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacol. tool compound and tested in a mouse model of AD (Tg2576) in vivo.

European Journal of Medicinal Chemistry published new progress about Alzheimer disease. 128577-47-9 belongs to class bromides-buliding-blocks, and the molecular formula is C9H8BrFO2, Recommanded Product: Methyl 4-(bromomethyl)-3-fluorobenzoate.

Referemce:
Bromide – Wikipedia,
bromide – Wiktionary

Yee, Ying K.; Bernstein, Peter R.; Adams, Edward J.; Brown, Frederick J.; Cronk, Laura A.; Hebbel, Kevin C.; Vacek, Edward P.; Krell, Robert D.; Snyder, David W. published the artcile< A novel series of selective leukotriene antagonists: exploration and optimization of the acidic region in 1,6-disubstituted indoles and indazoles>, Name: Methyl 4-(bromomethyl)-3-fluorobenzoate, the main research area is leukotriene antagonistic MSBAR indole indazole preparation; antiasthmatic indole indazole preparation.

A systematic structure-activity exploration of the carboxylic acid region in a series of indole- or indazole-derived leukotriene antagonists I [e.g., R = Me(CH2)3CHEt, X = CH, N, R1 = CO2H] led to several discoveries. Use of the 3-methoxy-p-tolyl fragment (illustrated in I) for connecting the indole and the acidic site provides the most potent carboxylic acids I (R = CO2H) tetrazoles I (R1 = tetraacyl) and aryl sulfonimides, e.g I (R = PhSO2NHCO). The aryl sulfonimides are 5-500 times more potent (in vitro and/or in vivo) than the corresponding carboxylic acids. The o-tolyl sulfonimides such as I (R = cyclohexylmethyl, X = N, R1 = 2-MeC6H4SO2NHCO) show greater oral potency than the Ph sulfonimides at a given level of in vitro activity. Acidic sulfone derivatives e.g., I [R = cyclopentylmethyl; X = CH, N; R1 = PhSO2CH(CO2Me)]-(Nu = CH(CO2CH3)SO2Ph) mimic the activity of the acidic imides.

Journal of Medicinal Chemistry published new progress about Antiasthmatics. 128577-47-9 belongs to class bromides-buliding-blocks, and the molecular formula is C9H8BrFO2, Name: Methyl 4-(bromomethyl)-3-fluorobenzoate.

Referemce:
Bromide – Wikipedia,
bromide – Wiktionary

Picard, Franck; Barassin, Stephan; Mokhtarian, Armand; Hartmann, Rolf W. published the artcile< Synthesis and Evaluation of 2'-Substituted 4-(4'-Carboxy- or 4'-carboxymethylbenzylidene)-N-acylpiperidines: Highly Potent and in Vivo Active Steroid 5α-Reductase Type 2 Inhibitors>, Application In Synthesis of 128577-47-9, the main research area is acylpiperidine carboxybenzylidene preparation steroid reductase inhibitor.

Sixteen N-acylpiperidines I (R1 = Ph2CH, Ph2CHCH2, dicyclohexylmethyl, 1-adamantyl; R2 = H, F, MeO; R3 = H, HO2C; R4 = H, HO2C, HO2CCH2) and II (R5 = Ph2CH, Ph2N, Me3CO, 1-adamantyl), bearing carboxylic acid moieties, were synthesized and evaluated for inhibition of rat and human steroid 5α-reductase isoenzymes types 1 and 2. In the dicyclohexylacetyl series (R1 = dicyclohexylmethyl), fluorination in the 2-position of the benzene nucleus, exchange of the carboxy group by a carboxymethyl moiety, and combination of both structural modifications led to highly active inhibitors of the human type 2 isoenzyme [IC50 values: I [R2 = F, R3 = H, R4 = HO2C; (III)], 11 nM; I (R2 = R3 = H, R4 = HO2CCH2), 6 nM; I (R2 = F, R3 = H, R4 = HO2CCH2), 7 nM; finasteride, 5 nM]. In vivo all compounds tested markedly reduced the prostate weights in castrated testosterone-treated rats. Oral activity was shown for compound I (R1 = dicyclohexylmethyl, R2 = R3 = H, R4 = HO2C). From the finding that III is active in the rat, although it is a rather poor inhibitor of the rat enzyme and is a strong inhibitor of the human enzyme, it is concluded that it should be highly potent in men.

Journal of Medicinal Chemistry published new progress about Benign prostatic hyperplasia. 128577-47-9 belongs to class bromides-buliding-blocks, and the molecular formula is C9H8BrFO2, Application In Synthesis of 128577-47-9.

Referemce:
Bromide – Wikipedia,
bromide – Wiktionary

Gaisina, Irina N.; Peet, Norton P.; Wong, Letitia; Schafer, Adam M.; Cheng, Han; Anantpadma, Manu; Davey, Robert A.; Thatcher, Gregory R. J.; Rong, Lijun published the artcile< Discovery and Structural Optimization of 4-(Aminomethyl)benzamides as Potent Entry Inhibitors of Ebola and Marburg Virus Infections>, Computed Properties of 128577-47-9, the main research area is aminomethyl benzamide derivative preparation Ebola Marburg virus infection.

The recent Ebola epidemics in West Africa underscore the great need for effective and practical therapies for future Ebola virus outbreaks. We have discovered a new series of remarkably potent small mol. inhibitors of Ebola virus entry. These 4-(aminomethyl)benzamide-based inhibitors are also effective against Marburg virus. Synthetic routes to these compounds allowed for the preparation of a wide variety of structures, including a conformationally restrained subset of indolines (compounds 41-50). Compounds 20, 23, 32, 33, and 35 are superior inhibitors of Ebola (Mayinga) and Marburg (Angola) infectious viruses. Representative compounds (20, 32, and 35) have shown good metabolic stability in plasma and liver microsomes (rat and human), and 32 did not inhibit CYP3A4 nor CYP2C9. These 4-(aminomethyl)benzamides are suitable for further optimization as inhibitors of filovirus entry, with the potential to be developed as therapeutic agents for the treatment and control of Ebola virus infections.

Journal of Medicinal Chemistry published new progress about Antiviral agents. 128577-47-9 belongs to class bromides-buliding-blocks, and the molecular formula is C9H8BrFO2, Computed Properties of 128577-47-9.

Referemce:
Bromide – Wikipedia,
bromide – Wiktionary

Lu, Dehua; Qu, Lailiang; Wang, Cheng; Luo, Heng; Li, Shang; Yin, Fucheng; Liu, Xingchen; Chen, Xinye; Luo, Zhongwen; Cui, Ningjie; Peng, Wan; Ji, Limei; Kong, Lingyi; Wang, Xiaobing published the artcile< Harmine-based dual inhibitors targeting histone deacetylase (HDAC) and DNA as a promising strategy for cancer therapy>, Safety of Methyl 4-(bromomethyl)-3-fluorobenzoate, the main research area is cancer therapy histone deacetylase harmine DNA damage; Cancer; DNA; DNA damage; HDAC; Harmine.

Overexpression of histone deacetylases (HDACs) are observed in different types of cancers, but histone deacetylase inhibitors (HDACIs) have not shown significant efficacy as monotherapy against solid tumors. Recently, studies demonstrated that it is promising to combine HDACIs with DNA damage agents to improve DNA damage level to gain better effect on treating solid tumor. Harmine has been demonstrated to cause DNA damage by intercalating DNA. Therefore, we designed a series of harmine-based inhibitors targeting HDAC and DNA with multi-target strategy, the most potential compound 27 could bind to DNA and cause DNA damage. Furthermore 27 caused cells apoptosis through p53 signaling pathway, and exhibited significant anti-proliferation effects against HCT-116 cells (IC50 = 1.41 μM). As a DNA damage agent, 27 displayed low toxicity in normal cells. Compound 27 was demonstrated as a dual inhibitor targeting HDAC (HDAC1 IC50 = 0.022 μM and HDAC6 IC50 = 0.45 μM) and DNA, and had the potential in the treatment of solid tumor.

Bioorganic Chemistry published new progress about Acetylation. 128577-47-9 belongs to class bromides-buliding-blocks, and the molecular formula is C9H8BrFO2, Safety of Methyl 4-(bromomethyl)-3-fluorobenzoate.

Referemce:
Bromide – Wikipedia,
bromide – Wiktionary

Shen, Sida; Benoy, Veronick; Bergman, Joel A.; Kalin, Jay H.; Frojuello, Mariana; Vistoli, Giulio; Haeck, Wanda; Van Den Bosch, Ludo; Kozikowski, Alan P. published the artcile< Bicyclic-Capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot-Marie-Tooth Disease>, Product Details of C9H8BrFO2, the main research area is histone deacetylase inhibitor neuroprotectant; Charcot−Marie−Tooth disease; Selective histone deacetylase 6 inhibitor; hydroxamic acid; mitochondrial axonal transport; mutant HSPB1-expressing DRG neurons; tubulin acetylation.

Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacol. treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacol. therapy. Therefore, the authors aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochem. properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, the authors developed several analogs that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound I that possesses improved biochem., functional, and druglike properties compared to tubastatin A.

ACS Chemical Neuroscience published new progress about Charcot-Marie-Tooth disease. 128577-47-9 belongs to class bromides-buliding-blocks, and the molecular formula is C9H8BrFO2, Product Details of C9H8BrFO2.

Referemce:
Bromide – Wikipedia,
bromide – Wiktionary

Schmidt, Jurema; Rotter, Marco; Weiser, Tim; Wittmann, Sandra; Weizel, Lilia; Kaiser, Astrid; Heering, Jan; Goebel, Tamara; Angioni, Carlo; Wurglics, Mario; Paulke, Alexander; Geisslinger, Gerd; Kahnt, Astrid; Steinhilber, Dieter; Proschak, Ewgenij; Merk, Daniel published the artcile< A Dual Modulator of Farnesoid X Receptor and Soluble Epoxide Hydrolase To Counter Nonalcoholic Steatohepatitis>, Application of C9H8BrFO2, the main research area is benzylbenzamide dual modulator analog preparation nonalcoholic steatohepatitis; dual modulator analog FXR sEH benzylbenzamide analog pharmacokinetics.

Nonalcoholic steatohepatitis arising from Western diet and lifestyle is characterized by accumulation of fat in liver causing inflammation and fibrosis. It evolves as serious health burden with alarming incidence, but there is no satisfying pharmacol. therapy to date. Considering the disease’s multifactorial nature, modulation of multiple targets might provide superior therapeutic efficacy. In particular, farnesoid X receptor (FXR) activation that revealed antisteatotic and antifibrotic effects in clin. trials combined with inhibition of soluble epoxide hydrolase (sEH) as anti-inflammatory strategy promises synergies. To exploit this dual concept, we developed agents exerting partial FXR agonism and sEH inhibitory activity. Merging known pharmacophores and systematic exploration of the structure-activity relationship on both targets produced dual modulators with low nanomolar potency. Extensive in vitro characterization confirmed high dual efficacy in cellular context combined with low toxicity, and pilot in vivo data revealed favorable pharmacokinetics as well as engagement on both targets in vivo.

Journal of Medicinal Chemistry published new progress about Antifibrotic agents. 128577-47-9 belongs to class bromides-buliding-blocks, and the molecular formula is C9H8BrFO2, Application of C9H8BrFO2.

Referemce:
Bromide – Wikipedia,
bromide – Wiktionary

Shen, Sida; Picci, Cristina; Ustinova, Kseniya; Benoy, Veronick; Kutil, Zsofia; Zhang, Guiping; Tavares, Mauricio T.; Pavlicek, Jiri; Zimprich, Chad A.; Robers, Matthew B.; Van Den Bosch, Ludo; Barinka, Cyril; Langley, Brett; Kozikowski, Alan P. published the artcile< Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot-Marie-Tooth Type 2A Mouse Model>, Computed Properties of 128577-47-9, the main research area is tetrahydroquinoline phenylhydroxamate synthesis SW101 HDAC6 neurodegenerative disorder; Charcot Marie Tooth disease tetrahydroquinoline Structure activity.

Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (1a), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot-Marie-Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (1s), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 (1a). X-ray crystallog. data reveal the mol. basis of HDAC6 inhibition by SW-101 (1s). Importantly, we demonstrate that SW-101 (1s) treatment elevates the impaired level of acetylated α-tubulin in the distal sciatic nerve, counteracts progressive motor dysfunction, and ameliorates neuropathic symptoms in a CMT2A mouse model bearing mutant MFN2. Taken together, these results bode well for the further development of SW-101 (1s) as a disease-modifying HDAC6i.

Journal of Medicinal Chemistry published new progress about Charcot-Marie-Tooth disease. 128577-47-9 belongs to class bromides-buliding-blocks, and the molecular formula is C9H8BrFO2, Computed Properties of 128577-47-9.

Referemce:
Bromide – Wikipedia,
bromide – Wiktionary