Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype.
Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype.
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DOI：
10.1016/j.bmcl.2011.09.049
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发表时间：
2011-11-15
影响因子：
2.7
通讯作者：
Roberts, Edward
中科院分区：
文献类型：
--
作者：
Urbano, Mariangela;Guerrero, Miguel;Velaparthi, Subash;Crisp, Melissa;Chase, Peter;Hodder, Peter;Schaeffer, Marie-Therese;Brown, Steven;Rosen, Hugh;Roberts, Edward
高亲和力和选择性S1 P4受体（S1 P4-R）小分子激动剂可能是重要的原理验证工具，用于阐明受体生物学功能和作用，以评估S1 P4-R在不同疾病领域的治疗潜力，包括治疗病毒感染和血小板减少症。我们的实验室进行了分子库-小分子库的高通量筛选活动，并鉴定了（2 Z，5 Z）-5-（（1-（2-氟苯基）-2，5-二甲基-1H-吡咯-3-基）亚甲基）-3-甲基-2-（甲基亚氨基）噻唑烷-4-酮作为与文献S1 P4-R调节剂不同的有前景的S1 P4-R激动剂。合理的化学修饰的命中允许鉴定一个有前途的铅分子与低纳摩尔S1 P4-R激动剂活性和精致的选择性超过其他S1 P1 - 3，5-Rs家族成员。本文公开的先导分子构成了探索S1 P4-R信号级联的作用和阐明受体功能的分子基础的有价值的药理学工具。
High affinity and selective S1P4 receptor (S1P4–R) small molecule agonists may be important proof-of-principle tools used to clarify the receptor biological function and effects to assess the therapeutic potential of the S1P4–R in diverse disease areas including treatment of viral infections and thrombocytopenia. A high-throughput screening campaign of the Molecular Libraries-Small Molecule Repository was carried out by our laboratories and identified (2Z,5Z)-5-((1-(2-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)-3-methyl-2-(methylimino) thiazolidin-4-one as a promising S1P4–R agonist hit distinct from literature S1P4–R modulators. Rational chemical modifications of the hit allowed the identification of a promising lead molecule with low nanomolar S1P4–R agonist activity and exquisite selectivity over the other S1P1-3,5–Rs family members. The lead molecule herein disclosed constitutes a valuable pharmacological tool to explore the effects of the S1P4–R signaling cascade and elucidate the molecular basis of the receptor function.
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影响因子：
2.7
作者：
Clemens, JJ;Davis, MD;Macdonald, TL
通讯作者：
Macdonald, TL
影响因子：
4.4
作者：
Toman, RE;Spiegel, S
通讯作者：
Spiegel, S
第一个报道的有效和选择性鞘氨醇1-磷酸4（S1P4）受体拮抗剂的发现，设计和合成。
影响因子：
2.7
作者：
Guerrero, Miguel;Urbano, Mariangela;Velaparthi, Subash;Zhao, Jian;Schaeffer, Marie-Therese;Brown, Steven;Rosen, Hugh;Roberts, Edward
通讯作者：
Roberts, Edward
DOI：
10.1038/nrd2356
发表时间：
2009-04
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
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影响因子：
2.7
作者：
Hanessian, Stephen;Charron, Guillaume;Guerini, Danilo
通讯作者：
Guerini, Danilo