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Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-26 , DOI: 10.1021/acs.jmedchem.9b02004 Simona Di Martino , Piero Tardia , Vincenzo Cilibrasi , Samantha Caputo , Marco Mazzonna , Debora Russo , Ilaria Penna , Natalia Realini , Natasha Margaroli , Marco Migliore , Daniela Pizzirani , Giuliana Ottonello , Sine Mandrup Bertozzi , Andrea Armirotti , Duc Nguyen 1 , Ying Sun 2 , Ernesto R Bongarzone 1 , Peter Lansbury 3 , Min Liu 3 , Renato Skerlj 3 , Rita Scarpelli
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-26 , DOI: 10.1021/acs.jmedchem.9b02004 Simona Di Martino , Piero Tardia , Vincenzo Cilibrasi , Samantha Caputo , Marco Mazzonna , Debora Russo , Ilaria Penna , Natalia Realini , Natasha Margaroli , Marco Migliore , Daniela Pizzirani , Giuliana Ottonello , Sine Mandrup Bertozzi , Andrea Armirotti , Duc Nguyen 1 , Ying Sun 2 , Ernesto R Bongarzone 1 , Peter Lansbury 3 , Min Liu 3 , Renato Skerlj 3 , Rita Scarpelli
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Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m, where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher’s and Krabbe’s diseases. After daily intraperitoneal administration at 90 mg kg–1, 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathogenesis.
中文翻译：
口服生物可利用的苯并恶唑酮甲酰胺和中枢神经系统渗透酸神经酰胺酶抑制剂的铅优化。
鞘脂（SphLs）是一类各种各样的分子，受复杂的酶促途径网络调节。这些途径的紊乱导致脂质积累和几种SphL相关疾病的发作。酸性神经酰胺酶是调节神经酰胺和糖鞘脂代谢的关键酶之一，它们是SphL家族的重要成员。在本文中，我们描述了导致哌啶22m的苯并恶唑酮羧酰胺的前导优化研究，其中我们证明了参与神经病性溶酶体贮积病（LSD），高雪氏症和克拉伯氏病的两种动物模型中的靶标参与。每日腹膜内给药90 mg kg –1之后，22m显着降低了4L; C *小鼠的有毒脂质葡萄糖基鞘氨醇（GluSph）和Twitcher小鼠的半乳糖基鞘氨醇（GalSph）的脑水平。我们认为22m是一种先导分子，可以进一步开发用于纠正严重神经系统LSD，其中GluSph或GalSph在疾病发病机理中起着重要作用。
更新日期：2020-03-27
中文翻译：
口服生物可利用的苯并恶唑酮甲酰胺和中枢神经系统渗透酸神经酰胺酶抑制剂的铅优化。
鞘脂（SphLs）是一类各种各样的分子，受复杂的酶促途径网络调节。这些途径的紊乱导致脂质积累和几种SphL相关疾病的发作。酸性神经酰胺酶是调节神经酰胺和糖鞘脂代谢的关键酶之一，它们是SphL家族的重要成员。在本文中，我们描述了导致哌啶22m的苯并恶唑酮羧酰胺的前导优化研究，其中我们证明了参与神经病性溶酶体贮积病（LSD），高雪氏症和克拉伯氏病的两种动物模型中的靶标参与。每日腹膜内给药90 mg kg –1之后，22m显着降低了4L; C *小鼠的有毒脂质葡萄糖基鞘氨醇（GluSph）和Twitcher小鼠的半乳糖基鞘氨醇（GalSph）的脑水平。我们认为22m是一种先导分子，可以进一步开发用于纠正严重神经系统LSD，其中GluSph或GalSph在疾病发病机理中起着重要作用。
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