Improvement of hERG-ROMK index of spirocyclic ROMK inhibitors through scaffold optimization and incorporation of novel pharmacophores
| Autor: | Haifeng Tang, Zack Zhiqiang Guo, Lee-Yuh Pai, Adam B. Weinglass, Xin Gu, Shuzhi Dong, Alexander Pasternak, Yang Yu, Kathleen A. Sullivan, Mengwei Hu, Kelsey VanGelder, Gloria J. Zingaro, Sophie Roy, Jessica Liu, Qinghong Fu, Birgit T. Priest, Michael Margulis, Brande Thomas-Fowlkes, Pierre Morissette, Robin E. Haimbach, Zhicai Wu, Juliann Ehrhart, Karen Owens, Caryn Hampton, Zhi-Cai Shi, Jessica Frie, Ron Ferguson, Shiyao Xu, Vincent Tong |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
ERG1 Potassium Channel Scaffold Clinical Biochemistry hERG Pharmaceutical Science Pharmacology Biochemistry Structure-Activity Relationship 03 medical and health sciences Dogs 0302 clinical medicine Thiadiazoles In vivo Rats Inbred SHR Drug Discovery Potassium Channel Blockers medicine Animals Structure–activity relationship Spiro Compounds Potassium Channels Inwardly Rectifying Molecular Biology biology Chemistry Organic Chemistry Potassium channel blocker Rats Disease Models Animal Pyrimidines 030104 developmental biology 030220 oncology & carcinogenesis Hypertension ROMK biology.protein Molecular Medicine Pharmacophore Half-Life medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 27:2559-2566 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2017.03.086 |
| Popis: | SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model. |
| Databáze: | OpenAIRE |
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