Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes

Wu Y.; Aquino C.J.; Cowan D.J.; Anderson D.L.; Ambroso J.L.; Bishop M.J.; Boros E.E.; Chen L.; Cunningham A.; Dobbins R.L.; Feldman P.L.; Harston L.T.; Kaldor I.W.; Klein R.; Liang X.; McIntyre M.S.; Merrill C.L.; Patterson K.M.; Prescott J.S.; Ray J.S.; Roller S.G.; Yao X.; Young A.; Yuen J.; Collins J.L.

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Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes

机译：发现一种用于治疗2型糖尿病的高效，不可吸收的根尖钠依赖性胆汁酸转运蛋白抑制剂（GSK2330672）

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The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.

机译：根尖钠依赖性胆汁酸转运蛋白（ASBT）通过门静脉将胆汁盐从胃肠道（GI）腔输送到肝脏。多家制药公司已经开发出ASBT与肝胆固醇代谢之间的生理联系，从而开展了ASBT抑制剂作为降脂剂的临床研究。尽管已证明了适度的脂质作用，但相对未开发ASBT抑制剂治疗2型糖尿病的潜在效用。我们启动了一项领先的优化工作，重点是从第一代抑制剂264W94（1）开始鉴定有效的，不可吸收的ASBT抑制剂。广泛的SAR研究最终发现了GSK2330672（56）作为一种强效，不可吸收的ASBT抑制剂，可降低2型糖尿病动物模型中的葡萄糖，并显示出极好的可开发性，可用于评估不可吸收的ASBT抑制剂治疗糖尿病的潜在治疗作用。 2型糖尿病患者。

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《Journal of Medicinal Chemistry》 |2013年第12期|共21页
作者
Wu Y.; Aquino C.J.; Cowan D.J.; Anderson D.L.; Ambroso J.L.; Bishop M.J.; Boros E.E.; Chen L.; Cunningham A.; Dobbins R.L.; Feldman P.L.; Harston L.T.; Kaldor I.W.; Klein R.; Liang X.; McIntyre M.S.; Merrill C.L.; Patterson K.M.; Prescott J.S.; Ray J.S.; Roller S.G.; Yao X.; Young A.; Yuen J.; Collins J.L.;
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Discovery; sodium-dependent; nonabsorbable;

机译：发现;钠依赖性;不可吸收;

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1. Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes [J] . Wu Y., Aquino C.J., Cowan D.J., Journal of Medicinal Chemistry . 2013,第12期

机译：发现一种用于治疗2型糖尿病的高效，不可吸收的根尖钠依赖性胆汁酸转运蛋白抑制剂（GSK2330672）
2. Zhang, L.a b , Wang, Y.b , Xu, H.a b , Shi, Y.b c , Liu, B.b , Wei, Q.b , Xu, W.b c , Tang, L.b c , Wang, J.a , Zhao, G.b Discovery of 6-deoxydapagliflozin as a highly potent sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes [J] . ZhangL., WangY., XuH., Medicinal chemistry . 2014,第3期

机译：Zhang，La b，Wang，Yb，Xu，Ha b，Shi，Yb c，Liu，Bb，Wei，Qb，Xu，Wb c，Tang，Lb c，Wang，Ja，Zhao，Gb发现6-脱氧达格列净高效钠依赖性葡萄糖共转运蛋白2（SGLT2）抑制剂，用于治疗2型糖尿病
3. Glucuronidation Converting Methyl 1-(3,4-Dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate(S-8921)to a Potent Apical Sodium-Dependent Bile Acid Transporter Inhibitor,Resulting in a Hypocholesterolemic Action [J] . Shingo Sakamoto, Hiroyuki Kusuhara, Kenji Miyata The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics . 2007,第2期

机译：葡萄糖醛酸化作用将1-（3,4-二甲氧基苯基）-3-（3-乙基戊酰基）-4-羟基-6,7,8-三甲氧基-2-萘甲酸甲酯（S-8921）转化为有效的根尖钠依赖性胆汁酸转运蛋白抑制剂，导致降胆固醇
4. Assessment of inhibitory effect of many therapeutically important drugs on bile acid transport by NTCP, BSEP and other transporters [C] . K. MAEDA, Y. TIAN, S. MITA, International Bile Acid Meeting . 2007

机译：NTCP，BSEP和其他转运蛋白对许多治疗重要药物对胆汁酸输送的抑制作用的评估
5. Understanding structure-function relationships and protein stability of the human apical sodium-dependent bile acid transporter (ASBT, SLC10A2). [D] . Claro da Silva, Tatiana. 2011

机译：了解人心钠依赖性胆汁酸转运蛋白（ASBT，SLC10A2）的结构-功能关系和蛋白质稳定性。
6. Safety tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial [O] . Renger G. Tiessen, Ciara A. Kennedy, Bradley T. Keller, 2018

机译：在健康成年人和2型糖尿病患者中使用Volixibat抑制根尖钠依赖性胆汁酸转运蛋白的安全性耐受性和药效学：一项随机安慰剂对照试验
7. Faculty Opinions recommendation of Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial. [O] . Carlos Aguilar-Salinas 2019

机译：教师意见的建议在健康的成人和2型糖尿病患者中与volxibat的安全性，耐受性和药效动性的安全性，耐受性和药效动性和药效动性，患有型糖尿病患者：随机安慰剂对照试验。

Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes

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