Discovery of 1-(1H-indazol-4-yl)-3-((1-phenyl-1H-pyrazol-5-yl)methyl) ureas as potent and thermoneutral TRPV1 antagonists

Kang, Jin Mi; Kwon, Sun Ok; Ann, Jihyae; Blumberg, Peter M.; Ha, Hee-Jin; Yoo, Youngdong; Frank-Foltyn, Robert; Lesch, B.; Bahrenberg, Gregor; Stockhausen, Hannelore; Christoph, Thomas; Lee, Jeeyeon

doi:10.1016/j.bmcl.2020.127548

Cited by 8 publications

(4 citation statements)

References 27 publications

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“…It should also be noted that the 5-alkoxy-1-arylpyrazoles obtained in this work differ in their effect on the TRPV1 ion channel from the antagonists of the group of carboxamide-(I) and urea-substituted (II) pyrazoles (Figure 1). [19,[22][23][24] In addition, the proposed TRPV1 modulators are distinguished by their structural simplicity and, accordingly, high synthetic accessibility from commercially available reagents in one step.…”

Section: Discussionmentioning

confidence: 99%

“…One part of the compound contains a lipophilic side chain (apolar part), and on the other side there is a more polar (het)aromatic group (polar part). Among the found chemotypes of TRPV1 modulators, [16] we have highlighted the group of carboxamide-(I) and urea-substituted (II) pyrazoles [19,[22][23][24] (Figure 1) as the most promising for analgesics development, since the pyrazole core is a part of various known analgesics, for example, celecoxib, mavacoxib, metamizole, propyphenazone, aminophenazone and etc. Note that the mechanism of action has not been reliably established for analgesics of the pyrazolone group.…”

Section: Introductionmentioning

confidence: 99%

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5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

et al. 2023

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Chemoselective O‐alkylation of 1‐aryl‐3‐polyfluoroalkylpyrazol‐5‐oles under basic conditions resulted in a series of 5‐alkoxypyrazoles (26 derivatives). They showed an acceptable ADME profile (in silico) and can be considered as drug‐like. In experiments in vivo (CD‐1 mice), it was found that the obtained compounds do not have toxic properties at a dose of more than 150 mg/kg (for most compounds at a dose of >300 mg/kg, and for lead compounds – >600 mg/kg). 22 Compounds from this series demonstrated from moderate to high analgesic effects (28–104 % at 1 h and 37–109 % at 2 h after administration) in vivo in the hot plate test (SD rats, 15 mg/kg, intraperitoneal (ip)). The lead compound was 4‐([1‐phenyl‐3‐(trifluoromethyl)pyrazol‐5‐yl]oxy)butan‐1‐ol, which not only increased the latent period in the hot plate test by 103 % at both measurement points but also showed a pronounced analgesic effect under conditions of capsaicin‐induced nociception (CD‐1 mice, 15 mg/kg, ip). According to molecular modeling, all synthesized compounds can interact with the TRPV1 ion channel. This biological target was confirmed in in vitro experiments on Chinese hamster ovary cells expressing rTRPV1. 5‐Alkoxypyrazoles were partial agonists of the TRPV1 ion channel in various degree, and the most active was the same pyrazole as in in vivo tests.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

et al. 2023

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“…Transient receptor potential vanilloid 1 (TRPV1) expressed in primary sensory neurons triggers nociception (Aghazadeh Tabrizi et al, 2017). Kang et al (2020) developed pyrazolyl‐indazole derivatives as potent non‐opioid analgesics with TRPV1 blocking activity for the treatment of neuropathic pain. Compounds 173 and 174 (Figure 18) exhibited great antagonistic activity against h TRPV with Ki 50 of 0.3 and 0.4 nM, respectively.…”

Section: Analgesic Activity Of Some Indazole Derivativesmentioning

confidence: 99%

“…Compounds 173 and 174 (Figure 18) exhibited great antagonistic activity against h TRPV with Ki 50 of 0.3 and 0.4 nM, respectively. Oral administration of compound 174 with capsaicin (given i.p) caused anti‐hyperthermia with fall in body temperature to its neutral temperature in vivo which signified its efficacy as potent anti‐nociceptive (Kang et al, 2020).…”

Section: Analgesic Activity Of Some Indazole Derivativesmentioning

confidence: 99%

A review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspective

Mal

Malik

Mahapatra

et al. 2022

Drug Development Research

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With different nitrogen-containing heterocyclic moieties, Indazoles earn one of the places among the top investigated molecules in medicinal research. Indazole, an important fused aromatic heterocyclic system containing benzene and pyrazole ring with a chemical formula of C 7 H 6 N 2 , is also called benzopyrazole. Indazoles consist of three tautomeric forms in which 1H-tautomers (indazoles) and 2H-tautomers (isoindazoles) exist in all phases. The tautomerism in indazoles greatly influences synthesis, reactivity, physical and even the biological properties of indazoles.The thermodynamic internal energy calculation of these tautomers points view 1H-indazole as the predominant and stable form over 2H-indazole. The natural source of indazole is limited and exists in alkaloidal nature (i.e., nigellidine, nigeglanine, nigellicine, etc.) found from Nigella plants. Some of the FDA-approved drugs like Axitinib, Entrectinib, Niraparib, Benzydamine, and Granisetron are being used to treat renal cell cancer, non-small cell lung cancer (NSCLC), epithelial ovarian cancer, chronic inflammation, chemotherapy-induced nausea, vomiting, and many more uses. Besides all these advantages regarding its biological activity, the main issue about indazoles is the less abundance in plant sources, and their synthetic derivatives also often face problems with low yield. In this review article, we discuss its chemistry, tautomerism along with their effects, different schematics for the synthesis of indazole derivatives, and their different biological activities.

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Organocatalyzed, Three‐Component Construction of Cyanopyrazoles Using Diazoacetonitrile

Dhami,

Kumar,

Nasreen Hisana

et al. 2024

Adv Synth Catal

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An organocatalyzed three‐component protocol using diazoacetonitrile to access a wide range of cyanopyrazole derivatives has been reported herein. This strategy, which proceeds through a piperidine‐catalyzed Knoevenagel condensation/formal [3+2] cycloaddition/dehydrocyanation sequence, provides an efficient route to construct dicyanopyrazoles from aldehydes, malononitrile, and diazoacetonitrile regioselectively. Interestingly, by engaging cyanoacetate and cyanoacetamide in this protocol, we could achieve cyanopyrazole esters and carboxamides.

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Discovery of 1-(1H-indazol-4-yl)-3-((1-phenyl-1H-pyrazol-5-yl)methyl) ureas as potent and thermoneutral TRPV1 antagonists

Cited by 8 publications

References 27 publications

5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

A review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspective

Organocatalyzed, Three‐Component Construction of Cyanopyrazoles Using Diazoacetonitrile

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