Efficient Synthesis of Novel NK<sub>1</sub> Receptor Antagonists:  Selective 1,4-Addition of Grignard Reagents to 6-Chloronicotinic Acid Derivatives

Hoffmann-Emery, Fabienne; Hilpert, Hans; Scalone, Michelangelo; Waldmeier, Pius

doi:10.1021/jo0523666

Cited by 33 publications

(20 citation statements)

References 29 publications

(25 reference statements)

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“…A CETP Inhibitor (2), which will be referenced CETP(2) (37), and a NK1 Receptor Antagonist (38), which will be referenced NK1(1), were selected. CETP(2) has a melting point ( T m ) of T m = 142°C, and that of NK1(1) is T m = 130°C.…”

Section: Methodsmentioning

confidence: 99%

Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions

et al. 2010

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PurposeDevelopment of a method to assess the drug/polymer miscibility and stability of solid dispersions using a melt-based mixing method.MethodsAmorphous fractured films are prepared and characterized with Raman Microscopy in combination with Atomic Force Microscopy to discriminate between homogenously and heterogeneously mixed drug/polymer combinations. The homogenous combinations are analyzed further for physical stability under stress conditions, such as increased humidity or temperature.ResultsCombinations that have the potential to form a molecular disperse mixture are identified. Their potential to phase separate is determined through imaging at molecular length scales, which results in short observation time. De-mixing is quantified by phase separation analysis, and the drug/polymer combinations are ranked to identify the most stable combinations.ConclusionsThe presented results demonstrate that drug/polymer miscibility and stability of solid dispersions, with many mechanistic details, can be analyzed with Atomic Force Microscopy. The assay allows to identify well-miscible and stable combinations within hours or a few days.Electronic Supplementary MaterialThe online version of this article (doi:10.1007/s11095-010-0306-4) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions

et al. 2010

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“…To further support the proposed goal of our study, we used netupitant, a potent and selective NK 1 antagonist currently under clinical evaluation to treat chemotherapy-induced nausea and vomiting. Other compounds, such as TAK-637, have been evaluated in a variety of experimental models in vitro and in vivo (Venkova et al, 2002;Venkova and Greenwood-Van Meerveld, 2004;Hoffmann-Emery et al, 2006). For netupitant, the affinity for NK 1 receptors was found with a pK b of 8.87 in Chinese hamster ovary cells, whereas in vivo the compound inhibited SP-induced scratching, biting, and licking with a median effective dose of 0.5 mg/kg p.o.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effect of 5-Hydroxytryptamine 3 and Neurokinin 1 Receptor Antagonism in Rodent Models of Somatic and Visceral Pain

Meerveld

Mohammadi

Tyler

et al. 2014

J Pharmacol Exp Ther

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Synergistic activity has been observed between serotonergic 5-hydroxytryptamine 3 (5-HT 3 ) and tachykinergic neurokinin 1 (NK 1 ) receptor-mediated responses. This study investigated the efficacy of a 5-HT 3 antagonist, palonosetron, and a NK 1 antagonist, netupitant, alone or in combination in rodent models of somatic and visceral colonic hypersensitivity. In a rat model of experimental neuropathic pain, somatic hypersensitivity was quantified by the number of ipsilateral paw withdrawals to a von Frey filament (6g). Electrophysiologic responses were recorded in the dorsal horn neurons after mechanical or thermal stimuli. Acute colonic hypersensitivity was induced experimentally in rats by infusing dilute acetic acid (0.6%) directly into the colon. Colonic sensitivity was assessed by a visceromotor behavioral response quantified as the number of abdominal contractions in response to graded isobaric pressures (0-60 mm Hg) of colorectal distension. Palonosetron or netupitant was administered alone or in combination via oral gavage. When dosed alone, both significantly reduced somatic sensitivity, decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation, and caused significant (P , 0.05) inhibition of colonic hypersensitivity in a dose-dependent manner. The combined administration of palonosetron and netupitant at doses that were ineffective alone significantly reduced both somatic and visceral sensitivity and decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation. In summary, the combination of palonosetron with a NK 1 receptor antagonist showed synergistic analgesic activity in rodent models of somatic and visceral hypersensitivity, and may prove to be a useful therapeutic approach to treat pain associated with irritable bowel syndrome.

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“…An NK1 Receptor Antagonist, which will be referenced to as NK1(Ant) (27), and a CETP Inhibitor (28), which will be referenced to as CETP(Inh) were selected there. NK1(Ant) has a melting point (T m ) of T m = 130°C: the melting point of CETP(Inh) is T m = 142°C.…”

Section: Methodsmentioning

confidence: 99%

Rapid Assessment of Homogeneity and Stability of Amorphous Solid Dispersions by Atomic Force Microscopy—From Bench to Batch

et al. 2013

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PurposeTo verify the robustness and fundamental value of Atomic Force Microscopy (AFM) and AFM-based assays to rapidly examine the molecular homogeneity and physical stability of amorphous solid dispersions on Hot-Melt-Extrudates.MethodsAmorphous solid dispersions were prepared with a Hot-Melt Extruder (HME) and profiled by Raman Microscopy and AFM following a sequential analytical routine (Multi-Scale-Imaging-of-Miscibiliy (MIMix)). Extrudates were analyzed before and after incubation at elevated temperature and humidity. The data were compared with published results as collected on miniaturized melt models. The value of molecular phase separation rates for long term stability prediction was assessed.ResultsData recorded on the extrudates are consistent with those published, and they can be compared side by side. Such direct data comparisons allow the identification of possible sources of extrudate heterogeneities. The surface roughness analysis of fracture-exposed interfaces is a novel quantitative way to trace on the nanometer scale the efficiencies of differently conducted HME-processes. Molecular phase separation rates are shown to be relevant for long term stability predictions.ConclusionsThe AFM-based assessment of API:excipient combinations is a robust method to rapidly identify miscible and stable solid dispersions in a routine manner. It provides a novel analytical tool for the optimization of HME processes.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-013-1045-0) contains supplementary material, which is available to authorized users.

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Efficient Synthesis of Novel NK₁ Receptor Antagonists: Selective 1,4-Addition of Grignard Reagents to 6-Chloronicotinic Acid Derivatives

Cited by 33 publications

References 29 publications

Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions

Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions

Synergistic Effect of 5-Hydroxytryptamine 3 and Neurokinin 1 Receptor Antagonism in Rodent Models of Somatic and Visceral Pain

Rapid Assessment of Homogeneity and Stability of Amorphous Solid Dispersions by Atomic Force Microscopy—From Bench to Batch

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Efficient Synthesis of Novel NK1 Receptor Antagonists: Selective 1,4-Addition of Grignard Reagents to 6-Chloronicotinic Acid Derivatives

Cited by 33 publications

References 29 publications

Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions

Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions

Synergistic Effect of 5-Hydroxytryptamine 3 and Neurokinin 1 Receptor Antagonism in Rodent Models of Somatic and Visceral Pain

Rapid Assessment of Homogeneity and Stability of Amorphous Solid Dispersions by Atomic Force Microscopy—From Bench to Batch

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Efficient Synthesis of Novel NK₁ Receptor Antagonists: Selective 1,4-Addition of Grignard Reagents to 6-Chloronicotinic Acid Derivatives