Pharmacophore Identification and Scaffold Exploration to Discover Novel, Potent, and Chemically Stable Inhibitors of Acid Ceramidase in Melanoma Cells,Journal of Medicinal Chemistry

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Pharmacophore Identification and Scaffold Exploration to Discover Novel, Potent, and Chemically Stable Inhibitors of Acid Ceramidase in Melanoma Cells
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-06-27 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00472
Jose Antonio Ortega ₁ , Jose M. Arencibia ₁ , Giuseppina La Sala ₁ , Marco Borgogno ₁ , Inga Bauer ₂ , Luca Bono ₃ , Clarissa Braccia ₃ , Andrea Armirotti ₃ , Stefania Girotto ₂ , Anand Ganesan ₄ , Marco De Vivo _{1,

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Affiliation

Acid ceramidase (AC) hydrolyzes ceramides, which are central lipid messengers for metabolism and signaling of sphingolipids. A growing body of evidence links deregulation of sphingolipids to several diseases, including cancer. Indeed, AC expression is abnormally high in melanoma cells. AC inhibition may thus be key to treating malignant melanoma. Here, we have used a systematic scaffold exploration to design a general pharmacophore for AC inhibition. This pharmacophore comprises a 6 + 5 fused ring heterocycle linked to an aliphatic substituent via a urea moiety. We have thus identified the novel benzimidazole derivatives 10, 21, 27, and 30, which are highly potent AC inhibitors. Their chemical and metabolic stabilities are comparable or superior to those of previously reported AC inhibitors. Moreover, they are potent against endogenous AC in intact melanoma cells. These novel inhibitors merit further characterization and can serve as a promising starting point for the discovery of new antimelanoma therapeutics.

中文翻译：

药理学鉴定和支架探索，发现黑色素瘤细胞中酸性神经酰胺酶的新型，有效和化学稳定抑制剂

酸性神经酰胺酶（AC）水解神经酰胺，神经酰胺是鞘脂的代谢和信号传导的主要脂质信使。越来越多的证据将鞘脂的失调与包括癌症在内的多种疾病联系在一起。实际上，黑色素瘤细胞中AC表达异常高。因此，AC抑制可能是治疗恶性黑色素瘤的关键。在这里，我们已经使用系统的支架探索来设计用于AC抑制的通用药效团。该药效团包含通过尿素部分连接至脂族取代基的6 + 5稠环杂环。因此，我们已经确定了新的苯并咪唑衍生物10，21，27，和30，它们是高效的AC抑制剂。它们的化学和代谢稳定性与先前报道的AC抑制剂相当或更好。此外，它们在完整的黑色素瘤细胞中对内源性AC具有有效作用。这些新型抑制剂值得进一步表征，并且可以作为发现新的炭疽病治疗剂的有希望的起点。

更新日期：2017-06-28

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