Synthesis and biological evaluation of 6-aryl-6H-pyrrolo(3,4-d)pyridazine derivatives: high-affinity ligands to the alpha2delta subunit of voltage gated calcium channels.

Stearns BA; Anker N; Arruda JM; Campbell BT; Chen C; Cramer M; Hu T; Jiang X; Park K; Ren KK; Sablad M; Santini A; Schaffhauser H; Urban MO; Munoz B

首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Synthesis and biological evaluation of 6-aryl-6H-pyrrolo(3,4-d)pyridazine derivatives: high-affinity ligands to the alpha2delta subunit of voltage gated calcium channels.

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Synthesis and biological evaluation of 6-aryl-6H-pyrrolo(3,4-d)pyridazine derivatives: high-affinity ligands to the alpha2delta subunit of voltage gated calcium channels.

机译：6-芳基-6H-吡咯并（3,4-d）哒嗪衍生物的合成和生物学评估：电压门控钙通道的alpha2delta亚基的高亲和力配体。

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A novel class of 6-aryl-6H-pyrrolo[3,4-d]pyridazine ligands for the alpha2delta subunit of voltage-gated calcium channels has been described. Substitutions in the aryl ring of the molecule were generally not tolerated, and resulted in diminished binding to the alpha2delta subunit. Modifications to the pyridazine ring revealed numerous permissive substitutions, and detailed SAR studies were carried out in this portion of the molecule. Replacement of the pyridazine ring methyl group with an aminomethyl functionality provided greatly improved potency over the initial lead. The initial lead compound displayed good rat pharmacokinetic properties, and was shown to be efficacious in the Chung model for neuropathic pain in rats.

机译：已经描述了用于电压门控钙通道的α2δ亚基的一类新型的6-芳基-6H-吡咯并[3,4-d]哒嗪配体。通常不容许分子的芳基环中的取代，并且导致与α2δ亚基的结合减少。哒嗪环的修饰揭示了许多许可的取代，并且在该分子的这一部分中进行了详细的SAR研究。用氨基甲基官能团取代哒嗪环甲基基团，与最初的铅相比，效能大大提高。最初的铅化合物显示出良好的大鼠药代动力学特性，并且在Chung模型中对大鼠的神经性疼痛显示出有效的效果。

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来源
《Bioorganic and Medicinal Chemistry Letters》 |2004年第5期|共4页
作者
Stearns BA; Anker N; Arruda JM; Campbell BT; Chen C; Cramer M; Hu T; Jiang X; Park K; Ren KK; Sablad M; Santini A; Schaffhauser H; Urban MO; Munoz B;
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正文语种 eng
中图分类基础医学;
关键词
pyridazine; Synthesis; voltage gated calcium channel;

机译：哒嗪;合成;电压门控钙通道;

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1. Synthesis and biological evaluation of 6-aryl-6H-pyrrolo(3,4-d)pyridazine derivatives: high-affinity ligands to the alpha2delta subunit of voltage gated calcium channels. [J] . Stearns BA, Anker N, Arruda JM, Bioorganic and Medicinal Chemistry Letters . 2004,第5期

机译：6-芳基-6H-吡咯并（3,4-d）哒嗪衍生物的合成和生物学评估：电压门控钙通道的alpha2delta亚基的高亲和力配体。
2. N-Acridin-9-yl-butane-1,4-diamine derivatives: high-affinity ligands of the alpha2delta subunit of voltage gated calcium channels. [J] . Lim J, Stock N, Pracitto R, Bioorganic and Medicinal Chemistry Letters . 2004,第8期

机译：N-Acridin-9-基丁烷-1,4-二胺衍生物：电压门控钙通道的alpha2delta亚基的高亲和力配体。
3. Structure-activity relationships of alpha-amino acid ligands for the alpha2delta subunit of voltage-gated calcium channels. [J] . Mortell KH, Anderson DJ, Lynch JJ 3rd, Bioorganic and Medicinal Chemistry Letters . 2006,第5期

机译：电压门控钙通道的alpha2delta亚基的α-氨基酸配体的结构活性关系。
4. Drug discovery based on the structure of FKBP12:Design, synthesis and evaluation of L-1,4-thiazane-3-carboxylic acid derivatives as neuroimmunophilin ligands [C] . NIE AiHua, XIAO JunHai, WANG LiLi, 第四届国际分子模拟与信息技术应用学术会议（The 4th International Conference of Molecular Simulations and Applied Informatics Technologies）论文集 . 2008

机译：基于FKBP12结构的药物发现：作为神经免疫亲和素配体的L-1,4-噻嗪-3-羧酸衍生物的设计，合成和评估
5. I. Origin of the voltage dependence of G protein regulation of P/Q-type calcium channels. II. A new tail of Pax6 and its interaction with calcium channel beta subunits. [D] . Zhang, Yun. 2009

机译：I.G蛋白调节P / Q型钙通道的电压依赖性的起源。二。 Pax6的新尾巴及其与钙通道β亚基的相互作用。
6. Subunit composition of G(o) proteins functionally coupling galanin receptors to voltage-gated calcium channels. [O] . F Kalkbrenner, V E Degtiar, M Schenker, 1995

机译：G（o）蛋白质的亚基组成功能上将甘丙肽受体耦合至电压门控钙通道。
7. Proteolytic cleavage of the voltage-gated Ca2+ channel alpha2delta subunit: structural and functional features. [O] . Andrade, Arturo, Sandoval, Alejandro, Oviedo, Norma, 2007

机译：电压门控的Ca2 +通道alpha2delta亚基的蛋白水解裂解：结构和功能特征。

Synthesis and biological evaluation of 6-aryl-6H-pyrrolo(3,4-d)pyridazine derivatives: high-affinity ligands to the alpha2delta subunit of voltage gated calcium channels.

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