Further Studies on Arylpiperazinyl Alkyl Pyridazinones: Discovery of an Exceptionally Potent, Orally Active, Antinociceptive Agent in Thermally Induced Pain

Biancalani, Claudio; Giovannoni, Maria Paola; Pieretti, Stefano; Cesari, Nicoletta; Graziano, Alessia; Vergelli, Claudia; Cilibrizzi, Agostino; Gianuario, Amalia Di; Colucci, Mariantonella; Mangano, Giorgina; Garrone, Beatrice; Polenzani, Lorenzo; Piaz, Vittorio Dal

doi:10.1021/jm900458r

Cited by 40 publications

(38 citation statements)

References 39 publications

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“…The pyridazine moiety is a versatile scaffold to develop new biological active compounds with wide varieties of biological activities and also be used to link other pharmacophoric groups. Pyridazine derivatives have various biological properties like anti-viral, anti-cancer, anti-hypertensive, antiinflammatory, anti-microbial, anti-depressant, anti-HIV and other biological activities [50][51][52][53][54][55][56] . The polyfunctional 2H-pyrano [3,2- …”

Section: Discussionmentioning

confidence: 99%

Biological Potential and Chemical Properties of Pyridine and Piperidine Fused Pyridazine Compounds: Pyridopyridazine a Versatile Nucleus

Asif¹

2016

AJCPS

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Pyridopyridazine compounds are important nitrogen atom containing heterocyclic compounds due to their pharmacological versatility. This heterocycle system characterized a structural feature for different types of bioactive compounds that exhibiting various types of biological activities which make it an attractive scaffold for the design and development of new drug molecules. This article provided information about the pharmacological properties of pyridopyridazines derivatives.

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Section: Discussionmentioning

confidence: 99%

Biological Potential and Chemical Properties of Pyridine and Piperidine Fused Pyridazine Compounds: Pyridopyridazine a Versatile Nucleus

Asif¹

2016

AJCPS

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“…ET A receptor antagonists potentiate clonidine analgesia in mice [10] . Several 4-arylpiperazine derivatives that are structurally related to centhaquin are potent analgesics [32] . Therefore, in this study we were interested in determining whether centhaquin possesses analgesic properties.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a series of structurally similar arylpiperazines was reported [32] to possess potent antinociceptive properties.…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Analgesic Effect of Centhaquin in Mouse Tail Flick and Hot-Plate Tests

Andurkar

Gulati²

2011

Pharmacology

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Background: Centhaquin is a centrally acting hypotensive drug like clonidine. Clonidine also produces analgesia and hypothermia in mice and potentiates morphine analgesia. Clonidine analgesia is blocked by idazoxan and naloxone while it is potentiated by BQ123 and sulfisoxazole. This study was conducted to determine the analgesic and hypothermic properties of centhaquin, and to assess whether it potentiates morphine analgesia. Yohimbine (α₂-adrenergic antagonist), idazoxan (imidazoline/α₂-adrenergic antagonist), naloxone (opioid antagonist), and BQ123 and sulfisoxazole (endothelin ET_A antagonists) were used to study the involvement of these receptors in centhaquin analgesia and hypothermia. Methods: Analgesic (tail flick and hot-plate tests) latencies and body temperatures were measured in male Swiss Webster mice treated with vehicle plus centhaquin, antagonists plus centhaquin or centhaquin plus morphine. Results: Centhaquin produced dose-dependent analgesia which was partially blocked by yohimbine, idazoxan and naloxone. BQ123 and sulfisoxazole did not affect centhaquin analgesia. Morphine analgesia was not potentiated by centhaquin. Centhaquin produced mild hypothermia which was not blocked by yohimbine, idazoxan, naloxone, BQ123 or sulfisoxazole. Conclusions: This is the first report demonstrating the analgesic activity of centhaquin. The α₂-adrenergic, imidazoline and opioid receptors are involved in mediating centhaquin analgesia. Endothelin ET_A receptors do not play a role in centhaquin analgesia; centhaquin does not augment morphine analgesia.

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“…Products 2a – f were obtained by standard alkylation on precursors 1a – c [21–23], using appropriately substituted 2-chloro- N -phenylacetamides and K 2 CO 3 in anhydrous acetonitrile at reflux. The N-aryl derivatives 3a – f were obtained through a coupling reaction on 1a – c with commercially available phenylboronic acids in the presence of EtN 3 and (Ac) 2 Cu (Scheme 1).…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and analytical characterization of new thiazol-2-(3H)-ones as human neutrophil elastase (HNE) inhibitors

Crocetti

Bartolucci

Cilibrizzi

et al. 2017

Chemistry Central Journal

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Human neutrophil elastase (HNE) is a potent serine protease belonging to the chymotrypsin family and is involved in a variety of pathologies affecting the respiratory system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here the synthesis of new thiazol-2-(3H)-ones as an elaboration of potent HNE inhibitors with an isoxazol-5-(2H)-one scaffold that we recently identified. Two-dimensional NMR spectroscopic techniques and tandem mass spectrometry allowed us to correctly assign the structure of the final compounds arising from both tautomers of the thiazol-2-(3H)-one nucleus (N-3 of the thiazol-2-(3H)-one and 3-OH of the thiazole). All new compounds were tested as HNE inhibitors, and no activity was found at the highest concentration used (40 µM), demonstrating that the thiazol-2-(3H)-one is not a good scaffold for HNE inhibitors. Molecular modelling experiments indicate that the low-energy pose might limit the nucleophilic attack on the endocyclic carbonyl group of the thiazolone-based compounds by HNE catalytic Ser195, in contrast to isoxazol-5-(2H)-one analogues. Electronic supplementary materialThe online version of this article (10.1186/s13065-017-0358-1) contains supplementary material, which is available to authorized users.

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Further Studies on Arylpiperazinyl Alkyl Pyridazinones: Discovery of an Exceptionally Potent, Orally Active, Antinociceptive Agent in Thermally Induced Pain

Cited by 40 publications

References 39 publications

Biological Potential and Chemical Properties of Pyridine and Piperidine Fused Pyridazine Compounds: Pyridopyridazine a Versatile Nucleus

Biological Potential and Chemical Properties of Pyridine and Piperidine Fused Pyridazine Compounds: Pyridopyridazine a Versatile Nucleus

Assessment of the Analgesic Effect of Centhaquin in Mouse Tail Flick and Hot-Plate Tests

Synthesis and analytical characterization of new thiazol-2-(3H)-ones as human neutrophil elastase (HNE) inhibitors

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