Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Mölndal SE-43183, Sweden.
Early Clinical Development, Research and Early Development, Respiratory, Inflammation and Autoimmune (RIA), BioPharmaceuticals R&D, AstraZeneca, Mölndal SE-43183, Sweden.
J Med Chem. 2020 Sep 10;63(17):9705-9730. doi: 10.1021/acs.jmedchem.0c00828. Epub 2020 Aug 27.
Muscle atrophy and cachexia are common comorbidities among patients suffering from cancer, chronic obstructive pulmonary disease, and several other chronic diseases. The peptide hormone ghrelin exerts pleiotropic effects including the stimulation of growth hormone secretion and subsequent increase of insulin-like growth factor-1 levels, an important mediator of muscle growth and repair. Ghrelin also acts on inflammation, appetite, and adipogenesis and therefore has been considered a promising therapeutic target for catabolic conditions. We previously reported on the synthesis and properties of an indane based series of ghrelin receptor full agonists which led to a sustained increase of insulin-like growth factor-1 in a dog pharmacodynamic study. Herein we report on the identification of a series of pyrrolidine or piperidine based full agonists and attempted optimization to give compounds with profiles suitable for progression as clinical candidates.
肌肉萎缩和恶病质是癌症、慢性阻塞性肺疾病和其他几种慢性疾病患者常见的合并症。肽激素 ghrelin 发挥多种作用，包括刺激生长激素分泌和随后增加胰岛素样生长因子-1 水平，胰岛素样生长因子-1 是肌肉生长和修复的重要介质。Ghrelin 还作用于炎症、食欲和脂肪生成，因此被认为是治疗分解代谢状态的有希望的治疗靶点。我们之前报道了基于茚满的一系列 ghrelin 受体完全激动剂的合成和性质，这些激动剂导致犬药效学研究中胰岛素样生长因子-1 的持续增加。在此，我们报告了一系列吡咯烷或哌啶基完全激动剂的鉴定，并尝试优化以获得适合作为临床候选药物推进的化合物。
