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Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes.用于治疗糖尿病的苯并-[1,2,4]-三唑并-[1,4]-恶二嗪GPR142激动剂的发现与开发
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Tryptophan-sensing receptor GPR142 expression levels are directly regulated by proinflammatory cytokines in ghrelin-producing cells.色氨酸感应受体GPR142的表达水平在胃饥饿素产生细胞中受促炎细胞因子直接调控。
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GPR142 prompts glucagon-like Peptide-1 release from islets to improve β cell function.GPR142 促使胰岛分泌胰高血糖素样肽-1，从而改善β细胞功能。
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The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site.GPR139 的参考激动剂 1a 和 7c 以及色氨酸和苯丙氨酸共享一个共同的结合位点。
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本文引用的文献

1
Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes.用于治疗糖尿病的苯并-[1,2,4]-三唑并-[1,4]-恶二嗪GPR142激动剂的发现与开发
Bioorg Med Chem Lett. 2016 Jun 15;26(12):2947-2951. doi: 10.1016/j.bmcl.2016.04.018.
2
GPR142 Agonists Stimulate Glucose-Dependent Insulin Secretion via Gq-Dependent Signaling.GPR142激动剂通过Gq依赖性信号传导刺激葡萄糖依赖性胰岛素分泌。
PLoS One. 2016 Apr 22;11(4):e0154452. doi: 10.1371/journal.pone.0154452. eCollection 2016.
3
Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes.强效、选择性促生长激素释放激素受体3拮抗剂MK-1421作为2型糖尿病开发候选药物的发现。
ACS Med Chem Lett. 2015 Mar 18;6(5):513-7. doi: 10.1021/ml500514w. eCollection 2015 May 14.
4
Aminopyrazole-Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies.基于氨基吡唑-苯丙氨酸的GPR142激动剂：工具化合物的发现及体内药效学研究
ACS Med Chem Lett. 2013 May 1;4(9):829-34. doi: 10.1021/ml4000854. eCollection 2013 Sep 12.
5
Potent and Orally Bioavailable GPR142 Agonists as Novel Insulin Secretagogues for the Treatment of Type 2 Diabetes.强效且口服生物可利用的GPR142激动剂作为治疗2型糖尿病的新型胰岛素促分泌剂
ACS Med Chem Lett. 2013 Jun 17;4(8):790-4. doi: 10.1021/ml400186z. eCollection 2013 Aug 8.
6
Phenylalanine derivatives as GPR142 agonists for the treatment of type II diabetes.苯丙氨酸衍生物作为 GPR142 激动剂用于治疗 II 型糖尿病。
Bioorg Med Chem Lett. 2012 Oct 1;22(19):6218-23. doi: 10.1016/j.bmcl.2012.08.015. Epub 2012 Aug 10.
7
Discovery and optimization of a novel series of GPR142 agonists for the treatment of type 2 diabetes mellitus.发现并优化新型 GPR142 激动剂系列，用于治疗 2 型糖尿病。
Bioorg Med Chem Lett. 2012 Sep 15;22(18):5942-7. doi: 10.1016/j.bmcl.2012.07.063. Epub 2012 Jul 23.
8
Triazoloamides as potent γ-secretase modulators with reduced hERG liability.三唑酰胺类作为有效的γ-分泌酶调节剂，具有降低 hERG 相关的致心律失常性。
Bioorg Med Chem Lett. 2012 May 1;22(9):3140-6. doi: 10.1016/j.bmcl.2012.03.054. Epub 2012 Mar 21.
9
Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry.通过破坏分子平面性和对称性来提高小分子药物发现项目中的水溶性。
J Med Chem. 2011 Mar 24;54(6):1539-54. doi: 10.1021/jm101356p. Epub 2011 Feb 23.
10
Utility of unbound plasma drug levels and P-glycoprotein transport data in prediction of central nervous system exposure.游离血浆药物水平和P-糖蛋白转运数据在预测中枢神经系统暴露中的应用。
Xenobiotica. 2009 Sep;39(9):687-93. doi: 10.1080/00498250903015402.

用于治疗2型糖尿病的新型三唑类GPR142激动剂的发现与优化

Discovery and Optimization of a Novel Triazole Series of GPR142 Agonists for the Treatment of Type 2 Diabetes.

作者信息

Guo Liangqin, Parker Dann L, Zang Yi, Sweis Ramzi F, Liu Weiguo, Sherer Edward C, Buist Nicole, Terebetski Jenna, Kelly Terri, Bugianesi Randal, Priest Birgit T, Dingley Karen H, Li Xiaofang, Mitelman Stan, Salituro Gino, Trujillo Maria E, Pachanski Michele, Kirkland Melissa, Powles Mary Ann, Eiermann George J, Feng Yue, Shang Jin, Howard Andrew D, Ujjainwalla Feroze, Sinz Christopher J, Debenham John S, Edmondson Scott D, Nargund Ravi P, Hagmann William K, Li Derun

机构信息

Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.

出版信息

ACS Med Chem Lett. 2016 Oct 12;7(12):1107-1111. doi: 10.1021/acsmedchemlett.6b00314. eCollection 2016 Dec 8.

DOI:10.1021/acsmedchemlett.6b00314
PMID:27994747
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5150677/
Abstract

GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound suffered from poor metabolic stability and poor solubility. Lead optimization strategies to improve potency, efficacy, metabolic stability, and solubility are described. This optimization led to compound , which showed significant reduction of glucose excursion in wild-type but not in GPR142 deficient mice in an oral glucose tolerance test (oGTT) study. These studies provide strong evidence that reduction of glucose excursion through treatment with is GPR142-mediated, and GPR142 agonists could be used as a potential treatment for type 2 diabetes.

摘要

GPR142已被确定为治疗2型糖尿病（T2DM）的潜在葡萄糖刺激胰岛素分泌（GSIS）靶点。通过高通量筛选发现了一类三唑GPR142激动剂。先导化合物存在代谢稳定性差和溶解度低的问题。描述了提高效力、疗效、代谢稳定性和溶解度的先导优化策略。这种优化产生了化合物，在口服葡萄糖耐量试验（oGTT）研究中，该化合物在野生型小鼠中可显著降低血糖波动，但在GPR142基因敲除小鼠中则无此作用。这些研究提供了强有力的证据，表明通过化合物治疗降低血糖波动是由GPR142介导的，GPR142激动剂可作为2型糖尿病的潜在治疗药物。