Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics

Tang, Haifeng; Walsh, Shawn P.; Yan, Yan; Jesus, Reynalda K. de; Shahripour, Aurash; Teumelsan, Nardos; Zhu, Yang; Ha, Sookhee; Owens, Karen; Thomas-Fowlkes, Brande; Felix, John P.; Liu, Jessica; Köhler, Martin; Priest, Birgit T.; Bailey, Timothy D.; Brochu, Richard M.; Alonso-Galicia, Magdalena; Kaczorowski, Gregory J.; Roy, Sophie; Lu, Yang; Mills, Sander G.; García, María L.; Pasternak, Alexander

doi:10.1021/ml3000066

Cited by 47 publications

(45 citation statements)

References 20 publications

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“…The search for Kir1.1 inhibitors has provided a limited number of compounds with appropriate potency, selectivity, and physicochemical and pharmacokinetic properties to be used in proof of concept studies (Lewis et al, 2009;Bhave et al, 2011;Tang et al, 2012). Compound A represents the first Kir1.1 inhibitor that fulfils these criteria.…”

Section: Discussionmentioning

confidence: 99%

“…Despite all the evidence supporting ROMK as a novel therapeutic target, the development of selective channel inhibitors has only recently been attempted. In addition to the peptide tertiapin, which blocks with high affinity the rat but not the human channel (Jin and Lu, 1998;Felix et al, 2006), two independent groups have reported the identification of small molecule ROMK inhibitors (Lewis et al, 2009;Bhave et al, 2011;Tang et al, 2012).…”

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confidence: 99%

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Pharmacologic Inhibition of the Renal Outer Medullary Potassium Channel Causes Diuresis and Natriuresis in the Absence of Kaliuresis

García

Priest

Alonso-Galicia

et al. 2013

J Pharmacol Exp Ther

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The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacologic Inhibition of the Renal Outer Medullary Potassium Channel Causes Diuresis and Natriuresis in the Absence of Kaliuresis

García

Priest

Alonso-Galicia

et al. 2013

J Pharmacol Exp Ther

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“…of several nanomolar-affinity small-molecule ROMK antagonists (135). A high-throughput screen of ϳ1.5 million compounds revealed a hit containing a 4-nitrophenyl group identical to that found in VU590 ( Fig.…”

Section: Romk (Kir11)mentioning

confidence: 93%

Novel diuretic targets

Denton

Pao

Maduke

2013

American Journal of Physiology-Renal Physiology

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As the molecular revolution continues to inform a deeper understanding of disease mechanisms and pathways, there exist unprecedented opportunities for translating discoveries at the bench into novel therapies for improving human health. Despite the availability of several different classes of antihypertensive medications, only about half of the 67 million Americans with hypertension manage their blood pressure appropriately. A broader selection of structurally diverse antihypertensive drugs acting through different mechanisms would provide clinicians with greater flexibility in developing effective treatment regimens for an increasingly diverse and aging patient population. An emerging body of physiological, genetic, and pharmacological evidence has implicated several renal ion-transport proteins, or regulators thereof, as novel, yet clinically unexploited, diuretic targets. These include the renal outer medullary potassium channel, ROMK (Kir1.1), Kir4.1/5.1 potassium channels, ClC-Ka/b chloride channels, UTA/B urea transporters, the chloride/bicarbonate exchanger pendrin, and the STE20/SPS1-related proline/alanine-rich kinase (SPAK). The molecular pharmacology of these putative targets is poorly developed or lacking altogether; however, recent efforts by a few academic and pharmaceutical laboratories have begun to lessen this critical barrier. Here, we review the evidence in support of the aforementioned proteins as novel diuretic targets and highlight examples where progress toward developing small-molecule pharmacology has been made.

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“…Merck Research Laboratories reported [39] the isolation and structure elucidation of a 1% impurity in a renal outer medullary potassium channel (ROMK or Kir1.1) HTS hit. Even though this hit impurity presented twin toxicophores it was turned into a useful lead.…”

Section: Challenges For Academic Drug Discoverymentioning

confidence: 99%

Academic drug discovery: current status and prospects

Everett¹

2015

Expert Opinion on Drug Discovery

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Introduction. The contraction in pharmaceutical drug discovery operations in the past decade has been counter--balanced by a significant rise in the number of academic drug discovery groups. In addition, pharmaceutical companies that used to operate in completely independent, vertically--integrated operations for drug discovery are now collaborating more with each other, and with academic groups. We are in a new era of drug discovery.Areas Covered. This review provides an overview of the current status of academic drug discovery groups, their achievements and the challenges they face,, together with perspectives on ways to achieve improved outcomes.Expert Opinion. Academic groups have made important contributions to drug discovery, from its earliest days and continue to do so today. However, modern drug discovery and development is exceedingly complex, and has high failure rates, principally because human biology is complex and poorly understood.

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Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics

Cited by 47 publications

References 20 publications

Pharmacologic Inhibition of the Renal Outer Medullary Potassium Channel Causes Diuresis and Natriuresis in the Absence of Kaliuresis

Pharmacologic Inhibition of the Renal Outer Medullary Potassium Channel Causes Diuresis and Natriuresis in the Absence of Kaliuresis

Novel diuretic targets

Academic drug discovery: current status and prospects

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