Aminopyrazoles with high affinity for the human neuropeptide Y5 receptor

Kordik, Cheryl P.; Luo, Chi; Zanoni, Brian C.; Dax, Scott L.; McNally, James J.; Lovenberg, Timothy W.; Wilson, Sandy J.; Reitz, Allen B.

doi:10.1016/s0960-894x(01)00448-6

Cited by 38 publications

(29 citation statements)

References 21 publications

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“…Selected bond lengths, bond and torsion angles are presented in Table 2. Hydrogen bonds 102.1 (2) 102.0 C(7)-C(6)-C (5) 102.5(2) 103.1 N(2)-C(7)-C (8) 120.8 (2) 122.2 N(2)-C(7)-C (6) 113.9(2) 113.1 C(8)-C(7)-C (6) 125.3(2) 124.7 C(9)-C(8)-C (7) 120.5(2) 120.9…”

Section: Resultsmentioning

confidence: 99%

“…Also pyrazole and derivatives thereof have been found to posses biological activities, such as medicinal and pesticidal activities [4][5][6][7]. Up to now, however, the investigations on triazole derivatives are mainly concentrated on such compounds that with the triazole nucleus as the sole bioactive group, and reports on triazole compounds containing both triazole and pyrazole functionalities in a single molecule are scarce.…”

Section: Introductionmentioning

confidence: 99%

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Experimental, theoretical and biological activity study on 1-(4,5-dihydro-3-arylpyrazol-1-yl)-2-(1H-1,2,4-triazol-1-yl)-ethanone

Huang

et al. 2006

Struct Chem

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Four compounds have been synthesized and characterized by 1 H NMR spectroscopy and elemental analyses, among which 1-(4,5-dihydro-3-phenyl-pyrazol-1-yl)-2-(1H-1,2,4-triazol-1-yl)ethanone 3a was further confirmed by X-ray crystallographic analysis. The biological activities of these compounds were tested, with the result that they displayed moderate fungicidal activities. In addition, a MO calculations using density functional theory (DFT) at B3LYP/6-31G * level have also been carried out, and the structure-activity relationships for these compounds are discussed.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Experimental, theoretical and biological activity study on 1-(4,5-dihydro-3-arylpyrazol-1-yl)-2-(1H-1,2,4-triazol-1-yl)-ethanone

Huang

et al. 2006

Struct Chem

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“…Related pyrazoles with N-methyl substituents, either on the NH2 or in the sulfonamide, provide derivatives with reduced affinity for the Y5 receptor. 127 For the treatment of cardiac arrhythmia, the KV1.5 channel antagonist 126 (the active enantiomer) showed long half-life and adequate bioavailability. 128 One of the most prominent biological properties of aminopyrazoles is as anticancer drugs.…”

Section: Directly Linkedmentioning

confidence: 99%

A review of recent progress (2002-2012) on the biological activities of pyrazoles

Pérez-Fernández¹,

Goya²,

Elguero³

2013

Arkivoc

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Dedicated to Professor Rosa M. Claramunt on the occasion of her 65 th anniversary AbstractIn this review, we report the structures of 243 pyrazoles with their corresponding biological activities. All of them are represented around the common structure of the pyrazole ring even in those cases where the heterocycle is only a minor part of the molecule. The classification we have used is based on chemical structure considerations and not in terms of the therapeutic area which is the more common approach. Some general conclusions have been drawn linking structures with activities.

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“…Two screening hits were reported by a group at R.W. Johnson, the nanomolar aminopyrazole lead was improved to yield (10) with Y5 affinity of 10 nM, while the 1 μM benzoindolylamine lead was improved to yield (11) with a 1 nM Y5 affinity [96,97]. A third series, the aminotetralins was also worked on by the R. W. Johnson group, resulting in a 1 nM antagonist [98,99].…”

Section: Y5 Antagonistsmentioning

confidence: 99%

“…A Y5 specific PET ligand, [ 11 C]MK-0233 (31), was developed and used to determine that single doses of MK-0557 (30) achieved greater 90% receptor occupancy 24 hrs post dose [28]. Table 4 presents [88] (10) 10 nM [96] (11) 1 nM [97] (12) 21 nM Y1,Y2 selective ip reduces FI [99] (13 [28] the in vitro characteristics the Y5 clinical compounds. In a 12 week proof-of concept/dose-ranging study in obese patients; 1, 5, and 25 mg of MK-0557 (30) caused significant weight loss, and the data indicated that efficacy was maximal with 1 mg [28].…”

Section: Y5 Antagonistsmentioning

confidence: 99%

NPY Y1 and Y5 Receptor Selective Antagonists as Anti-Obesity Drugs

MacNeil¹

2007

CTMC

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A combination of pharmacological and genetic studies in mice confirmed that the Y1 and Y5 receptors mediate the potent orexigenic actions of exogenous NPY. Although the physiological role of NPY in causing obesity is less clear, potent and selective antagonists of both Y1 and Y5 have been developed. Some of the NPY antagonists have suitable pharmacokinetic (PK) properties that allowed them to be evaluated in various rodent models of obesity. Several different Y1 and Y5 antagonists cause weight loss in rodent models, though confirmation that these effects are mechanism based has been limited. One Y5 antagonist, MK-0557 was evaluated in a 1-yr clinical trial and found to cause modest weight loss. Optimal NPY antagonist therapeutics for obesity may require blockade of both the Y1 and Y5 receptors.

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Aminopyrazoles with high affinity for the human neuropeptide Y5 receptor

Cited by 38 publications

References 21 publications

Experimental, theoretical and biological activity study on 1-(4,5-dihydro-3-arylpyrazol-1-yl)-2-(1H-1,2,4-triazol-1-yl)-ethanone

Experimental, theoretical and biological activity study on 1-(4,5-dihydro-3-arylpyrazol-1-yl)-2-(1H-1,2,4-triazol-1-yl)-ethanone

A review of recent progress (2002-2012) on the biological activities of pyrazoles

NPY Y1 and Y5 Receptor Selective Antagonists as Anti-Obesity Drugs

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