Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation

Walsh, Shawn P.; Shahripour, Aurash; Tang, Haifeng; Jesus, Reynalda K. de; Teumelsan, Nardos; Zhu, Yang; Frie, Jessica L.; Priest, Birgit T.; Swensen, Andrew M.; Alonso-Galicia, Magdalena; Felix, John P.; Brochu, Richard M.; Bailey, Timothy D.; Thomas-Fowlkes, Brande; Zhou, Xiaoyan; Pai, Lee-Yuh; Hampton, Caryn; Hernandez, Melba; Owens, Karen; Ehrhart, Juliann; Roy, Sophie; Kaczorowski, Gregory J.; Lu, Yang; García, María L.; Pasternak, Alexander

doi:10.1016/j.bmcl.2016.03.035

Cited by 9 publications

(4 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The benzimidazole series was further optimized for metabolic stability and its ancillary pharmacology profile, in particular the safety margin between hERG and HeLa potencies. The inhibition of the hERG (human ether-a-go-go gene) potassium channel is associated with QT interval prolongation (measured on an electrocardiogram, ECG) and the potentially lethal ventricular tachycardia torsades de pointes (TdP). , The safety margin determined by the ratio of the hERG IC 50 to the Hela IC 50 was used as a comparator to rank order compounds for further evaluation. − Initially, activity against hERG was assessed using a fluorescence polarization-binding assay (Table ), and subsequent electrophysiological readouts of hERG channel function were measured for key compounds via Q-Patch and Manual Patch clamp assays (Table ).…”

Section: Resultsmentioning

confidence: 99%

Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme

et al. 2021

View full text Add to dashboard Cite

Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme that mediates the rate-limiting step in the metabolism of l-tryptophan to kynurenine, has been widely explored as a potential immunotherapeutic target in oncology. We developed a class of inhibitors with a conformationally constrained bicyclo[3.1.0]hexane core. These potently inhibited IDO1 in a cellular context by binding to the apoenzyme, as elucidated by biochemical characterization and X-ray crystallography. A SKOV3 tumor model was instrumental in differentiating compounds, leading to the identification of IACS-9779 (62) and IACS-70465 (71). IACS-70465 has excellent cellular potency, a robust pharmacodynamic response, and in a human whole blood assay was more potent than linrodostat (BMS-986205). IACS-9779 with a predicted human efficacious once daily dose below 1 mg/kg to sustain >90% inhibition of IDO1 displayed an acceptable safety margin in rodent toxicology and dog cardiovascular studies to support advancement into preclinical safety evaluation for human development.

show abstract

Section: Resultsmentioning

confidence: 99%

Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In particular, it would be important to compare the efficacy of MK-7145 and loop diuretics for diuretic resistance, and in patients with kidney failure. The search for Kir1.1 inhibitors has identified a limited number of compounds with appropriate potency, selectivity, and physical-chemical and pharmacokinetic properties to be used in proof of concept studies (Lewis et al, 2009;Bhave et al, 2010;Tang et al, 2012Tang et al, , 2013Tang et al, , 2016Garcia and Kaczorowski, 2014;Walsh et al, 2015Walsh et al, , 2016. MK-7145 represents the most potent and selective Kir1.1 inhibitor disclosed to date.…”

Section: Discussionmentioning

confidence: 99%

The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartters Syndrome Type II Phenotype

Hampton

Zhou

Priest

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter's syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter's syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter's syndrome type II features are manifested on exposure to ROMK inhibitors.

show abstract

“…Fourth, homozygous ROMK knockout rats exhibited severe volume depletion, while the heterozygous knockouts presented with reduced blood pressure and incidence of kidney injury . Small-molecule pharmacological blockade of ROMK has demonstrated increased diuresis (equivalent to loop diuretics), reduced blood pressure, decreased potassium wasting, and decreased end-organ damage in preclinical species. − Furthermore, the Denton Lab at Vanderbilt − and Merck − carried out independent medicinal chemistry campaigns to identify ROMK inhibitors. Merck subsequently progressed MK-7145 into clinical trials, which demonstrated increased diuresis and reduced blood pressure, , but was subsequently withdrawn from further study.…”

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.

View full text Add to dashboard Cite

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.

show abstract

Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation

Cited by 9 publications

References 21 publications

Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme

Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme

The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartters Syndrome Type II Phenotype

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

Contact Info

Product

Resources

About