Synthesis and Biological Evaluation of the 1-Arylpyrazole Class of 蟽1 Receptor Antagonists: Identification of 4-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (

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• 作者：Jos茅 Luis D铆az ; Rosa Cuberes ; Joana Berrocal ; Montserrat Contijoch ; Ute Christmann ; Ariadna Fern谩ndez ; Adriana Port ; J枚rg Holenz ; Helmut Buschmann ; Christian Laggner ; Maria Teresa Serafini ; Javier Burgue帽o ; Daniel Zamanillo ; Manuel Merlos ; Jos茅 Miguel Vela ; Carmen Almansa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8211-8224
• 全文大小：577K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent 蟽₁ receptor (蟽₁R) antagonists are reported. The new compounds were evaluated in vitro in human 蟽₁R and guinea pig 蟽₂ receptor (蟽₂R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for 蟽₁R vs 蟽₂R. The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.