6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists

Sun, Wei; Kim, Hyo Shin; Lee, Sunho; Jung, A Young; Kim, Sung Eun; Ann, Jihyae; Yoon, Suyoung; Choi, Sun; Lee, Jin Hee; Blumberg, Peter M.; Frank-Foltyn, Robert; Bahrenberg, Gregor; Schiene, Klaus; Stockhausen, Hannelore; Christoph, Thomas; Frormann, Sven; Lee, Jeeyeon

doi:10.1016/j.bmcl.2014.12.086

Cited by 5 publications

(4 citation statements)

References 19 publications

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“…In particular, the N‐[{2‐(4‐methylpiperidin‐1‐yl)‐6‐(trifluoromethyl)‐pyridin‐3‐yl}methyl]‐N’‐(6,6‐fused heterocyclic) urea (e.g., compound 53 ; Fig. ) showed highly potent hTRPV1 antagonism to capsaicin (IC 50 = 0.2 nM), heat, and was efficacious in the formalin pain model . Molecular modeling analysis with hTRPV1 homology model supplies the binding mode of compound 53 with the receptor in which hydrogen bonding between the isoquinoline nitrogen and Ser512 is important for high potency.…”

Section: Medicinal Chemistry Of Trpv1 Antagonistsmentioning

confidence: 96%

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

106

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Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium-dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure-activity relationships (SARs) focusing on new strategies to target this channel.

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Section: Medicinal Chemistry Of Trpv1 Antagonistsmentioning

confidence: 96%

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

106

View full text Add to dashboard Cite

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“…Since the highest yield of 8-isoquinolinamine was less than 72%, such purity limited its industrial application. − Recrystallization, which had the advantages of high efficiency, cheapness, and simplicity, was undoubtedly a more suitable purification method . So pure solvents such as DMF, acetonitrile, and n -propanol, or mixed solvents composed of n -propanol and water all can be used to recrystallize the crude product to obtain high-purity 8-isoquinolinamine.…”

Section: Resultsmentioning

confidence: 99%

“…8-Isoquinolinamine (C 9 H 8 N 2 , CAS No. 23687-27-6, molecular weight 144.17 g·mol –1 , IUPAC name: isoquinoline, 8-amino-, molecular structure shown in Figure ) is a representative crystalline powder derivative of amine-containing heterocycles, which has been regarded as an indispensable raw material in the pharmaceutical industry, also belonging to a wide variety of naturally occuring alkaloids. − Several works have reported the synthesis methods of 8-isoquinolinamine; however, the crude product was purified by vacuum sublimation at 373.15 K followed by recrystallization from heptane or petroleum ether, resulting in the low yield of 53–72%. ,− Hence, it is necessary to recrystallize the product.…”

Section: Introductionmentioning

confidence: 99%

Solubility Data, Modeling, and Solvent Effect of 8-Isoquinolinamine in Four Mixed Solvents and Ten Monosolvents from 278.15 to 323.15 K

Yao

2022

J. Chem. Eng. Data

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The equilibrium solubility of 8-isoquinolinamine in methanol, ethanol, n-propanol, isopropanol, N,N-dimethylformamide (DMF), acetonitrile, acetone, propylene glycol (PG), ethylene glycol (EG), and water, and aqueous mixtures of methanol/ethanol/n-propanol/isopropanol plus water was experimentally measured by the isothermal saturation method at 278.15–323.15 K under 101.2 kPa. The mole fractions of 8-isoquinolinamine in monosolvents were obtained to be maximum in neat DMF. For the four binary mixed solvent systems, the amount of 8-isoquinolinamine dissolved in n-propanol + water is more than that in the other three systems. The mole fractions of 8-isoquinolinamine in pure solvents were correlated using the Apelblat model, van’t Hoff model, and Wilson model, and the calculated value of the Apelblat model was the closest to the experimental value. The Jouyban–Acree model, modified Apelblat–Jouyban–Acree model, and van’t Hoff–Jouyban–Acree model were applied to calculate the solubility of 8-isoquinolinamine in the four solvent mixtures. The feedback obtained by comparing the experimental data with the calculated data is that the calculated data from the Jouyban–Acree model was relatively close to the experimental results. Solvent effects as a powerful tool can be used to estimate interactions at the molecular level, and the results showed that solvent–solvent intermolecular interactions contribute to dissolution. van’t Hoff plots are adopted as a method to show the relationship between ln(x) and 1/T.

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“…Fused heterocylic compounds have long been known for their significant applications in pharmaceutical and biomedical industries. [1][2][3] They possess significant roles to serve as bioactive lead molecules [4] and molecular recognition events. [5] They are present in numerous natural products [6] agrochemicals [7] and pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

Investigation on Photophysical, Solvatochromism and Biological Significance of Substituted 2H‐Indazole Derivatives

2020

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The electronic properties of substituted 2H-indazoles were investigated for their photophysical behavior under isolated conditions and in solvent environment, both computationally and experimentally. DFT calculations with CAMÀ B3LYP functional and 6-311 + + G** basis set were performed in the ground and excited states. The effect of solvents on the low and high energy electronic states was studied by following the steady state absorption and fluorescence excitation and emission spectra. Solvatochromic interactions including general and specific solvent effects are reported along with the results of Lippert and E T (30) plots. The biological significance of these 2H-indazole derivatives was also investigated through docking studies. The interactions of 2H-indazole derivatives with the active site of subdomain II of human casein kinase (C2 K) alpha are reported.

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6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists

Cited by 5 publications

References 19 publications

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Solubility Data, Modeling, and Solvent Effect of 8-Isoquinolinamine in Four Mixed Solvents and Ten Monosolvents from 278.15 to 323.15 K

Investigation on Photophysical, Solvatochromism and Biological Significance of Substituted 2H‐Indazole Derivatives

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