Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

Nakajima Katsumasa; Chatelain Ricardo; Clairmont Kevin B.; Commerford Renee; Coppola Gary M.; Daniels Thomas; Forster Cornelia J.; Gilmore Thomas A.; Gong Yongjin; Jain Monish; Kanter Aaron; Kwak Youngshin; Li Jingzhou; Meyers Charles. D.; Neubert Alan D.; Szklennik Paul; Tedesco Vivienne; Thompson James; Truong David; Yang Qing; Hubbard Brian K.; Serrano-Wu Michael H.

首页> 外文期刊>Journal of Medicinal Chemistry >Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

【24h】

Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

机译：发现口服生物可利用的苯并咪唑二酰基甘油酰基转移酶1（DGAT1）抑制剂，抑制饮食诱导的肥胖犬和人类后甘油三酯的体重增加

获取原文

获取原文并翻译 | 示例

掌桥外文数据库（机构版） >>

开具论文收录证明 >>

文献代查 >>

页面导航

摘要
著录项
相似文献
相关主题

摘要

Modification of a gut restricted class of benziMidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes to 1 include bioisosteric replacement of the amide with oxadiazole and a,a-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both 1,and 9 can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only 9 was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. 9 has advanced to clinical investigation and successfully suppr8sed postprandial triglycerides during an acute meal challenge in humans.

机译：肠咪唑DGAT1抑制剂1的肠道限制类的改性LED良好的口服生物利用度。关键结构变化为1包括与羧酸的酰胺和A-二甲基化的生物蛋白酶替代，提高DGAT1效力和肠道渗透性。由于DGAT1在小肠中表达，均在1和9中表达，因此在大鼠和狗的急性口服脂质挑战期间可以抑制后甘油三酯。有趣的是，只发现9例有效地抑制体重增加相对于饮食诱导的肥胖犬模型的控制，表明DGAT1对体重控制的系统性抑制的重要性。 9在人类急性膳食挑战期间先进于临床调查，并成功抑制了黄甘油酯。

著录项

来源
《Journal of Medicinal Chemistry》 |2017年第11期|共8页
作者
Nakajima Katsumasa; Chatelain Ricardo; Clairmont Kevin B.; Commerford Renee; Coppola Gary M.; Daniels Thomas; Forster Cornelia J.; Gilmore Thomas A.; Gong Yongjin; Jain Monish; Kanter Aaron; Kwak Youngshin; Li Jingzhou; Meyers Charles. D.; Neubert Alan D.; Szklennik Paul; Tedesco Vivienne; Thompson James; Truong David; Yang Qing; Hubbard Brian K.; Serrano-Wu Michael H.;
展开▼
作者单位

Novartis Inst Biomed Res Global Discovery Chem 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Cardiovasc &

Metab 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Cardiovasc &

Metab 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Cardiovasc &

Metab 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Global Discovery Chem 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Cardiovasc &

Metab 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Global Discovery Chem 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Global Discovery Chem 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Global Discovery Chem 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res PK Sci 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Global Discovery Chem 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Global Discovery Chem 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Global Discovery Chem 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Translat Med 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Global Discovery Chem 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Global Discovery Chem 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Cardiovasc &

Metab 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Cardiovasc &

Metab 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Cardiovasc &

Metab 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Cardiovasc &

Metab 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Cardiovasc &

Metab 100 Technol Sq Cambridge MA 02139 USA;

Novartis Inst Biomed Res Global Discovery Chem 100 Technol Sq Cambridge MA 02139 USA;

展开▼
收录信息
原文格式 PDF
正文语种 eng
中图分类药学;
关键词

相似文献

外文文献
专利

1. Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans [J] . Nakajima Katsumasa, Chatelain Ricardo, Clairmont Kevin B., Journal of Medicinal Chemistry . 2017,第11期

机译：发现口服生物可利用的苯并咪唑二酰基甘油酰基转移酶1（DGAT1）抑制剂，抑制饮食诱导的肥胖犬和人类后甘油三酯的体重增加
2. A Novel Acyl-CoA: Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor, GSK2973980A, Inhibits Postprandial Triglycerides and Reduces Body Weight in a Rodent Diet-induced Obesity Model [J] . British Journal of Pharmaceutical Research . 2017,第6期

机译：新型酰基辅酶A：二酰基甘油酰基转移酶1（DGAT1）抑制剂GSK2973980A在啮齿类动物饮食诱发的肥胖模型中抑制餐后甘油三酸酯并降低体重
3. Discovery of dimethyl pent-4-ynoic acid derivatives, as potent and orally bioavailable DGAT1 inhibitors that suppress body weight in diet-induced mouse obesity model [J] . Yu Tao, Wu Chengde, Shih NengYang, Bioorganic and Medicinal Chemistry Letters . 2018,第10期

机译：发现二甲基PET-4-奈瑟酸衍生物，作为有效和口服生物可利用的DGAT1抑制剂，其在饮食诱导的小鼠肥胖模型中抑制体重
4. ZP2435 Decreases Body Weight Gain in Diet-Induced Obese Wistar Rats [C] . Lars Bo L. Hansen, Jens R. Daugaard American Peptide Symposium . 2011

机译：ZP2435降低饮食诱导的肥胖Wistar大鼠体重增加
5. Intestine-specific expression of acyl CoA:diacylglycerol acyltransferase 1 reverses resistance to diet-induced hepatic steatosis and obesity in Dgat1−/− mice [O] . Bonggi Lee, Angela M. Fast, Jiabin Zhu, 2010

机译：酰基辅酶A：二酰基甘油酰基转移酶1的肠特异性表达可逆转Dgat1-/-小鼠对饮食诱导的肝脂肪变性和肥胖的抵抗力
6. Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans [O] . -1

机译：发现口服生物可利用的苯并咪唑二酰基甘油酰基转移酶1（DGAT1）抑制剂，抑制饮食诱导的肥胖犬和人类后甘油三酯的体重增加

Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

摘要

著录项

相似文献

相关主题

期刊订阅