N-Substituted Nipecotic Acids as (S)-SNAP-5114 Analogues with Modified Lipophilic Domains.,ChemMedChem

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N-Substituted Nipecotic Acids as (S)-SNAP-5114 Analogues with Modified Lipophilic Domains.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-04-07 , DOI: 10.1002/cmdc.201900719
Michael C Böck ₁ , Georg Höfner ₁ , Klaus T Wanner ₁

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Potential mGAT4 inhibitors derived from the lead substance (S)-SNAP-5114 have been synthesized and characterized for their inhibitory potency. Variations from the parent compound included the substitution of one of its aromatic 4-methoxy and 4-methoxyphenyl groups, respectively, with a more polar moiety, including a carboxylic acid, alcohol, nitrile, carboxamide, sulfonamide, aldehyde or ketone function, or amino acid partial structures. Furthermore, it was investigated how the substitution of more than one of the aromatic 4-methoxy groups affects the potency and selectivity of the resulting compounds. Among the synthesized test substances (S)-1-{2-[(4-formylphenyl)bis(4-methoxyphenyl)-methoxy]ethyl}piperidine-3-carboxylic acid, that features a carbaldehyde function in place of one of the aromatic 4-methoxy moieties of (S)-SNAP-5114, was found to have a pIC50 value of 5.89±0.07, hence constituting a slightly more potent mGAT4 inhibitor than the parent substance while showing comparable subtype selectivity.

中文翻译：

N-取代的哌啶酸作为 (S)-SNAP-5114 类似物，具有修饰的亲脂性结构域。

源自先导物质 (S)-SNAP-5114 的潜在 mGAT4 抑制剂已被合成并表征其抑制效力。母体化合物的变体包括其芳香族 4-甲氧基和 4-甲氧基苯基之一分别被极性更大的部分取代，包括羧酸、醇、腈、甲酰胺、磺酰胺、醛或酮官能团或氨基酸部分结构。此外，还研究了多个芳香族 4-甲氧基的取代如何影响所得化合物的效力和选择性。在合成的测试物质(S)-1-{2-[(4-甲酰基苯基)双(4-甲氧基苯基)-甲氧基]乙基}哌啶-3-甲酸中，其特征是用甲醛官能团代替芳香族官能团之一(S)-SNAP-5114 的 4-甲氧基部分被发现具有 5.89±0.07 的 pIC50 值，因此构成比母体物质稍强的 mGAT4 抑制剂，同时显示出相当的亚型选择性。

更新日期：2020-04-07

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