Discovery of Small Molecule Renal Outer Medullary Potassium (ROMK) Channel Inhibitors: A Brief History of Medicinal Chemistry Approaches To Develop Novel Diuretic Therapeutics

Aretz, Christopher D.; Vadukoot, Anish K.; Hopkins, Corey R.

doi:10.1021/acs.jmedchem.8b01891

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…In contrast, individuals with only one mutated copy of KCNJ1 have a lower risk of hypertension and decreased blood pressure [9]. Because nearly all blood pressure lowering drugs exhibit unwanted side-effects, the development of ROMK inhibitors has been actively pursued [10,11]. A realization of this goal would also benefit from a deeper understanding of ROMK folding and assembly, as well as the conformational dynamics that mediate channel opening.…”

Section: Introductionmentioning

confidence: 99%

Complementary computational and experimental evaluation of missense variants in the ROMK potassium channel

et al. 2020

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The renal outer medullary potassium (ROMK) channel is essential for potassium transport in the kidney, and its dysfunction is associated with a salt-wasting disorder known as Bartter syndrome. Despite its physiological significance, we lack a mechanistic understanding of the molecular defects in ROMK underlying most Bartter syndrome-associated mutations. To this end, we employed a ROMK-dependent yeast growth assay and tested single amino acid variants selected by a series of computational tools representative of different approaches to predict each variants' pathogenicity. In one approach, we used in silico saturation mutagenesis, i.e. the scanning of all possible single amino acid substitutions at all sequence positions to estimate their impact on function, and then employed a new machine learning classifier known as Rhapsody. We also used two additional tools, EVmutation and Polyphen-2, which permitted us to make consensus predictions on the pathogenicity of single amino acid variants in ROMK. Experimental tests performed for selected mutants in different classes validated the vast majority of our predictions and provided insights into variants implicated in ROMK dysfunction. On a broader scope, our analysis suggests that consolidation of data from complementary computational approaches provides an improved and facile method to predict the severity of an amino acid substitution and may help accelerate the identification of disease-causing mutations in any protein. Author summaryAs the number of sequenced human genomes rises, a major challenge is to identify which single amino acid variations in a protein affect function and predispose individuals to disease. While predictive algorithms are available for this purpose, a comparative analysis of recently developed algorithms has not been adequately performed, nor is it clear whether combining algorithms would improve predictive power. To this end, we compared the efficacy of three publicly available algorithms and applied the results to Bartter syndrome, PLOS COMPUTATIONAL BIOLOGY PLOS Computational Biology | https://doi.Citation: Ponzoni L, Nguyen NH, Bahar I, Brodsky JL (2020) Complementary computational and experimental evaluation of missense variants in the ROMK potassium channel. PLoS Comput Biol 16 (4): e1007749. https://doi.org/10.a human disease for which numerous poorly-characterized single amino acid variants have been identified and for which there is no cure. In silico saturation mutagenesis, i.e., the computational prediction of pathogenesis for every possible amino acid substitution, allowed us to experimentally test predictions by measuring the activity of an ion channel linked to Bartter syndrome. Based on data from blinded experiments, we discovered that Rhapsody and EVmutation successfully predicted deleterious mutations. Moreover, Rhapsody-which takes into account evolutionary as well as structural and dynamic considerations-predicted that >90% of known Bartter syndrome mutations are deleterious. Overall, our data will aid investigators who wish...

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Section: Introductionmentioning

confidence: 99%

Complementary computational and experimental evaluation of missense variants in the ROMK potassium channel

et al. 2020

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“…These studies using knockout and transgenic UMOD mouse models suggest that umod plays an important role in the development of salt-sensitive hypertension, resulting primarily from sodium reabsorption via Na + K + -2Cl- cotransporter protein (NKCC2) and Na + -Cl- cotransporter protein ( 54 – 56 ). The mechanism by which UMOD has been shown to affect blood pressure is mainly the combination of TAL and DCT to modulate the activity of ion transport proteins in epithelial cells, including the renal outer medullary potassium channel (ROMK) ( 57 , 58 ), epithelial sodium channel (ENaC) ( 59 ), NKCC2 ( 60 ), and NCC ( 8 , 61 , 62 ), of which NKCC2 and NCC are the major transport proteins responsible for sodium reabsorption ( 63 ). Mutations in NKCC2 and malfunctions in its regulators are known to cause Bartter syndrome, a salt-depleting hypotensive disorder with reduced levels of UMOD, in addition to a significant reduction in NKCC2 phosphorylation in Umod(-/-) mice, where NKCC2 expression is not as strong as in WT mice, and conversely, mice with overexpressed UMOD exhibit salt-sensitive hypertension ( 64 – 66 ).…”

Section: Relationship Between Uromodulin and Various Cardiovascular D...mentioning

confidence: 99%

The role of uromodulin in cardiovascular disease: a review

Chen,

Zhong,

Zheng

et al. 2024

Front. Cardiovasc. Med.

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Uromodulin, also referred to as Tamm Horsfall protein (THP), is a renal protein exclusively synthesized by the kidneys and represents the predominant urinary protein under normal physiological conditions. It assumes a pivotal role within the renal system, contributing not only to ion transport and immune modulation but also serving as a critical factor in the prevention of urinary tract infections and kidney stone formation. Emerging evidence indicates that uromodulin may serve as a potential biomarker extending beyond renal function. Recent clinical investigations and Mendelian randomization studies have unveiled a discernible association between urinary regulatory protein levels and cardiovascular events and mortality. This review primarily delineates the intricate relationship between uromodulin and cardiovascular disease, elucidates its predictive utility as a novel biomarker for cardiovascular events, and delves into its involvement in various physiological and pathophysiological facets of the cardiovascular system, incorporating recent advancements in corresponding genetics.

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“…Merck subsequently progressed MK-7145 into clinical trials, which demonstrated increased diuresis and reduced blood pressure, , but was subsequently withdrawn from further study. The Shanghai Hengrui Pharmaceutical Company has also published on the discovery of ROMK inhibitors, and ROMK inhibition has been the subject of recent review articles. − This robust proof-of-concept strengthened our commitment to undertake a medicinal chemistry campaign in order to identify ROMK inhibitors that can help address the large unmet medical need for heart failure.…”

Section: Introductionmentioning

confidence: 99%

Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure

Richter,

Gunaga,

Yadav

et al. 2024

J. Med. Chem.

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Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.

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Discovery of Small Molecule Renal Outer Medullary Potassium (ROMK) Channel Inhibitors: A Brief History of Medicinal Chemistry Approaches To Develop Novel Diuretic Therapeutics

Cited by 5 publications

References 33 publications

Complementary computational and experimental evaluation of missense variants in the ROMK potassium channel

Complementary computational and experimental evaluation of missense variants in the ROMK potassium channel

The role of uromodulin in cardiovascular disease: a review

Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure

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