Abstract
Previously reported studies from these laboratories described the design of a novel series of high-affinity NK1 antagonists based on the 4,4-disubstituted piperidine ring system. Further structure-activity studies have now established that for high NK1 affinity the benzyl ether side chain must be 3,5-disubstituted and highly lipophilic, the optimal side chain being the 3, 5-bis(trifluoromethyl)benzyl ether, 12 (hNK1 IC50 = 0.95 nM). Additional studies have shown that this class of NK1 antagonist tolerates a wider range of substituents on the piperidine nitrogen, including acyl (38) (hNK1 IC50 = 5.3 nM) and sulfonyl (39) (hNK1 IC50 = 5.7 nM) derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID50 = 0.22 and 0.28 mg/kg, respectively).
MeSH terms
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Animals
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CHO Cells
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Capillary Permeability / drug effects
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Cricetinae
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Diterpenes / toxicity
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Esophagus / blood supply
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Esophagus / drug effects
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Guinea Pigs
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Inositol Phosphates / metabolism
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Male
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Neurokinin-1 Receptor Antagonists*
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology
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Radioligand Assay
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Receptors, Neurokinin-1 / biosynthesis
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / pharmacokinetics
Substances
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1-(4-(3,5-bis(trifluoromethyl)benzyloxymethyl)-4-phenylpiperidin-1-yl)-2-pyrrolidineacetamide
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4-(3,5-bis(trifluoromethyl)benzyloxymethyl)-1-(2-methylthiazol-5-ylmethyl)-4-phenylpiperidine
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Diterpenes
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Inositol Phosphates
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Neurokinin-1 Receptor Antagonists
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Piperidines
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Pyrrolidines
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Receptors, Neurokinin-1
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Thiazoles
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resiniferatoxin