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Discovery of ACH-000143: A Novel Potent and Peripherally Preferred Melatonin Receptor Agonist that Reduces Liver Triglycerides and Steatosis in Diet-Induced Obese Rats
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-02-08 , DOI: 10.1021/acs.jmedchem.0c00627 Marcos Antonio Ferreira 1 , Hatylas Azevedo 1 , Alessandra Mascarello 1 , Natanael Dante Segretti 1 , Elisa Russo 2 , Valter Russo 2 , Cristiano Ruch Werneck Guimarães 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-02-08 , DOI: 10.1021/acs.jmedchem.0c00627 Marcos Antonio Ferreira 1 , Hatylas Azevedo 1 , Alessandra Mascarello 1 , Natanael Dante Segretti 1 , Elisa Russo 2 , Valter Russo 2 , Cristiano Ruch Werneck Guimarães 1
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The modulation of melatonin signaling in peripheral tissues holds promise for treating metabolic diseases like obesity, diabetes, and nonalcoholic steatohepatitis. Here, several benzimidazole derivatives have been identified as novel agonists of the melatonin receptors MT1 and MT2. The lead compounds 10b, 15a, and 19a demonstrated subnanomolar potency at MT1/MT2 receptors, high oral bioavailability in rodents, peripherally preferred exposure, and excellent selectivity in a broad panel of targets. Two-month oral administration of 10b in high-fat diet rats led to a reduction in body weight gain similar to dapagliflozin with superior results on hepatic steatosis and triglyceride levels. An early toxicological assessment indicated that 10b (also codified as ACH-000143) was devoid of hERG binding, genotoxicity, and behavioral alterations at doses up to 100 mg/kg p.o., supporting further investigation of this compound as a drug candidate.
中文翻译：
ACH-000143 的发现：一种新型有效且外周首选的褪黑激素受体激动剂，可降低饮食引起的肥胖大鼠的肝脏甘油三酯和脂肪变性
外周组织中褪黑激素信号的调节有望治疗肥胖、糖尿病和非酒精性脂肪性肝炎等代谢性疾病。在此，几种苯并咪唑衍生物已被鉴定为褪黑激素受体 MT1 和 MT2 的新型激动剂。先导化合物10b 、 15a和19a表现出对 MT1/MT2 受体的亚纳摩尔效力、啮齿类动物的高口服生物利用度、外周首选暴露以及对广泛靶标的优异选择性。高脂肪饮食大鼠口服10b两个月可导致体重增加减少，与达格列净相似，对肝脂肪变性和甘油三酯水平具有优异的效果。早期毒理学评估表明， 10b （也编码为ACH-000143 ）在口服剂量高达 100 mg/kg 时没有 hERG 结合、遗传毒性和行为改变，支持对该化合物作为候选药物的进一步研究。
更新日期：2021-02-25
中文翻译：
ACH-000143 的发现：一种新型有效且外周首选的褪黑激素受体激动剂，可降低饮食引起的肥胖大鼠的肝脏甘油三酯和脂肪变性
外周组织中褪黑激素信号的调节有望治疗肥胖、糖尿病和非酒精性脂肪性肝炎等代谢性疾病。在此，几种苯并咪唑衍生物已被鉴定为褪黑激素受体 MT1 和 MT2 的新型激动剂。先导化合物10b 、 15a和19a表现出对 MT1/MT2 受体的亚纳摩尔效力、啮齿类动物的高口服生物利用度、外周首选暴露以及对广泛靶标的优异选择性。高脂肪饮食大鼠口服10b两个月可导致体重增加减少，与达格列净相似，对肝脂肪变性和甘油三酯水平具有优异的效果。早期毒理学评估表明， 10b （也编码为ACH-000143 ）在口服剂量高达 100 mg/kg 时没有 hERG 结合、遗传毒性和行为改变，支持对该化合物作为候选药物的进一步研究。
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