Improvement of hERG-ROMK index of spirocyclic ROMK inhibitors through scaffold optimization and incorporation of novel pharmacophores

  • Bioorg Med Chem Lett. 2017 Jun 1;27(11):2559-2566. doi: 10.1016/j.bmcl.2017.03.086.
Shuzhi Dong  1 ,  Kelsey VanGelder  2 ,  Zhi-Cai Shi  2 ,  Yang Yu  2 ,  Zhicai Wu  2 ,  Ron Ferguson  2 ,  Zack Zhiqiang Guo  2 ,  Haifeng Tang  2 ,  Jessica Frie  2 ,  Qinghong Fu  2 ,  Xin Gu  2 ,  Birgit T Priest  2 ,  Brande Thomas-Fowlkes  2 ,  Adam Weinglass  2 ,  Michael Margulis  2 ,  Jessica Liu  2 ,  Lee-Yuh Pai  2 ,  Caryn Hampton  2 ,  Robin E Haimbach  2 ,  Karen Owens  2 ,  Vincent Tong  2 ,  Shiyao Xu  2 ,  Mengwei Hu  2 ,  Gloria J Zingaro  2 ,  Pierre Morissette  2 ,  Juliann Ehrhart  2 ,  Sophie Roy  2 ,  Kathleen Sullivan  2 ,  Alexander Pasternak  2
Affiliations
  • 1. MRL, Merck & Co., Inc., Kenilworth, NJ 07033, USA. Electronic address: [email protected].
  • 2. MRL, Merck & Co., Inc., Kenilworth, NJ 07033, USA.
PMID: 28431879 DOI: 10.1016/j.bmcl.2017.03.086
Abstract

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.

Keywords
Diuresis; Heart failure; Hypertension; Natriuresis; ROMK; Spirocycle; hERG.
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