Medicinal Chemistry Department, Cardiovascular and Metabolic Diseases IMED Biotech Unit , AstraZeneca Gothenburg , 43183 Mölndal , Sweden.
Precision Medicine Laboratories, Precision Medicine and Genomics IMED Biotech Unit , AstraZeneca Gothenburg , 43183 Mölndal , Sweden.
J Med Chem. 2018 Jul 26;61(14):5974-5987. doi: 10.1021/acs.jmedchem.8b00322. Epub 2018 Jul 6.
Cachexia and muscle wasting are very common among patients suffering from cancer, chronic obstructive pulmonary disease, and other chronic diseases. Ghrelin stimulates growth hormone secretion via the ghrelin receptor, which subsequently leads to increase of IGF-1 plasma levels. The activation of the GH/IGF-1 axis leads to an increase of muscle mass and functional capacity. Ghrelin further acts on inflammation, appetite, and adipogenesis and for this reason was considered an important target to address catabolic conditions. We report the synthesis and properties of an indane based series of ghrelin receptor full agonists; they have been shown to generate a sustained increase of IGF-1 levels in dog and have been thoroughly investigated with respect to their functional activity.
恶病质和肌肉消耗在患有癌症、慢性阻塞性肺疾病和其他慢性疾病的患者中非常常见。胃饥饿素通过胃饥饿素受体刺激生长激素分泌，随后导致 IGF-1 血浆水平升高。GH/IGF-1 轴的激活导致肌肉质量和功能能力的增加。胃饥饿素进一步作用于炎症、食欲和脂肪生成，因此被认为是解决分解代谢状态的重要靶点。我们报告了基于茚满的胃饥饿素受体完全激动剂系列的合成和性质；它们已被证明可使犬 IGF-1 水平持续升高，并已对其功能活性进行了彻底研究。
