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A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-01 , DOI: 10.1021/acs.jmedchem.1c01856
David A Griffith 1 , David J Edmonds 1 , Jean-Philippe Fortin 1 , Amit S Kalgutkar 1 , J Brent Kuzmiski 1 , Paula M Loria 2 , Aditi R Saxena 1 , Scott W Bagley 2 , Clare Buckeridge 1 , John M Curto 2 , David R Derksen 2 , João M Dias 2 , Matthew C Griffor 2 , Seungil Han 2 , V Margaret Jackson 1 , Margaret S Landis 1 , Daniel Lettiere 2 , Chris Limberakis 2 , Yuhang Liu 2 , Alan M Mathiowetz 1 , Jayesh C Patel 3 , David W Piotrowski 2 , David A Price 1 , Roger B Ruggeri 1 , David A Tess 1
Affiliation  

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

中文翻译:

人胰高血糖素样肽-1受体的小分子口服激动剂

胰高血糖素样肽-1 受体 (GLP-1R) 的肽激动剂已经彻底改变了糖尿病治疗,但由于需要注射,它们的使用受到限制。在此,我们描述了口服生物可利用的小分子 GLP-1R 激动剂 PF-06882961 (danuglipron) 的发现。使用致敏的高通量筛选来鉴定基于 5-氟嘧啶的 GLP-1R 激动剂,这些激动剂经过优化以促进具有纳摩尔效力的内源性 GLP-1R 信号传导。羧酸部分的掺入提供了可观的 GLP-1R 效力增益,同时改善了脱靶药理学并降低了代谢清除率,最终导致了 danuglipron 的鉴定。Danuglipron 增加灵长类动物的胰岛素水平,但不增加啮齿动物,这可以通过受体诱变研究和低温电子显微镜结构来解释,该结构揭示了一个需要灵长类动物特异性色氨酸 33 残基的结合口袋。向健康人口服给予 danuglipron 会导致全身暴露量与剂量成比例增加 (NCT03309241)。这为针对经过充分验证的 GLP-1R 用于代谢健康的口服小分子疗法提供了机会。
更新日期:2022-06-01
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