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Identification of potent pyrazole based APELIN receptor (APJ) agonists.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-11-30 , DOI: 10.1016/j.bmc.2019.115237 Sanju Narayanan 1 , Vineetha Vasukuttan 1 , Sudarshan Rajagopal 2 , Rangan Maitra 1 , Scott P Runyon 1
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-11-30 , DOI: 10.1016/j.bmc.2019.115237 Sanju Narayanan 1 , Vineetha Vasukuttan 1 , Sudarshan Rajagopal 2 , Rangan Maitra 1 , Scott P Runyon 1
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The apelinergic system comprises the apelin receptor and its cognate apelin and elabela peptide ligands of various lengths. This system has become an increasingly attractive target for pulmonary and cardiometabolic diseases. Small molecule regulators of this receptor with good drug-like properties are needed. Recently, we discovered a novel pyrazole based small molecule agonist 8 of the apelin receptor (EC50 = 21.5 µM, Ki = 5.2 µM) through focused screening which was further optimized to initial lead 9 (EC50 = 0.800 µM, Ki = 1.3 µM). In our efforts to synthesize more potent agonists and to explore the structural features important for apelin receptor agonism, we carried out structural modifications at N1 of the pyrazole core as well as the amino acid side-chain of 9. Systematic modifications at these two positions provided potent small molecule agonists exhibiting EC50 values of <100 nM. Recruitment of β-arrestin as a measure of desensitization potential of select compounds was also investigated. Functional selectivity was a feature of several compounds with a bias towards calcium mobilization over β-arrestin recruitment. These compounds may be suitable as tools for in vivo studies of apelin receptor function.
中文翻译：
鉴定基于吡唑的强效APELIN受体（APJ）激动剂。
Apelinergic系统包含apelin受体及其相关的apelin和各种长度的elabela肽配体。该系统已成为针对肺部和心脏代谢疾病的越来越有吸引力的目标。需要具有良好药物样性质的该受体的小分子调节剂。最近，我们通过聚焦筛选发现了一种新型的基于apelin受体的吡唑基小分子激动剂8（EC50 = 21.5 µM，Ki = 5.2 µM），并进一步优化了初始铅9（EC50 = 0.800 µM，Ki = 1.3 µM）。为了合成更有效的激动剂并探索对apelin受体激动重要的结构特征，我们在吡唑核心的N1以及9位氨基酸的侧链上进行了结构修饰。在这两个位置上的系统修饰提供了有效的小分子激动剂，其EC50值小于100 nM。还研究了β-arrestin的招募，以衡量所选化合物的脱敏潜力。功能选择性是几种化合物的特征，与β-arrestin募集相比偏向于钙动员。这些化合物可能适合用作体内研究apelin受体功能的工具。
更新日期：2019-11-30
中文翻译：
鉴定基于吡唑的强效APELIN受体（APJ）激动剂。
Apelinergic系统包含apelin受体及其相关的apelin和各种长度的elabela肽配体。该系统已成为针对肺部和心脏代谢疾病的越来越有吸引力的目标。需要具有良好药物样性质的该受体的小分子调节剂。最近，我们通过聚焦筛选发现了一种新型的基于apelin受体的吡唑基小分子激动剂8（EC50 = 21.5 µM，Ki = 5.2 µM），并进一步优化了初始铅9（EC50 = 0.800 µM，Ki = 1.3 µM）。为了合成更有效的激动剂并探索对apelin受体激动重要的结构特征，我们在吡唑核心的N1以及9位氨基酸的侧链上进行了结构修饰。在这两个位置上的系统修饰提供了有效的小分子激动剂，其EC50值小于100 nM。还研究了β-arrestin的招募，以衡量所选化合物的脱敏潜力。功能选择性是几种化合物的特征，与β-arrestin募集相比偏向于钙动员。这些化合物可能适合用作体内研究apelin受体功能的工具。
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