Delving into the Latest Updates on Amiloride Hydrochloride with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

3,5-diamino-N-carbamimidoyl-6-chloropyrazine-2-carboxamide, Amiloride, Amiloride hydrochloride (USP)

+ [9]

Target

ENaCα

Mechanism

ENaCα inhibitors(sodium channel epithelial 1 subunit alpha inhibitors)

Therapeutic Areas

Cardiovascular Diseases

Active Indication

Heart FailureHypertension

Inactive Indication-

Originator Organization

Perrigo Co. Plc

Active Organization

Padagis US LLC

Inactive Organization-

Drug Highest PhaseApproved

First Approval Date

US (05 Oct 1981),

Heart FailureHypertension

RegulationOrphan Drug (US)

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Structure/Sequence

Molecular FormulaC6H8ClN7O

InChIKeyXSDQTOBWRPYKKA-UHFFFAOYSA-N

CAS Registry2609-46-3

View All Structures (2)

Resistant hypertension is defined as blood pressure that remains above goal despite concurrent use of three antihypertensive agents of different classes including diuretics. Patients with resistant hypertension has at least 1.5-fold higher cardiovascular risk than those with non-resistant hypertension. Therefore, controlling blood pressure is crucial in patients with resistant hypertension.
It has been unclear which antihypertensive agent should be added in patients who cannot reach target blood pressure despite use of three antihypertensive agents. There have been three randomized clinical trials that proved the efficacy of spironolactone in resistant hypertension, but they were small sized, comparison study to placebo. Recently published PATHWAY-2 study which compared the efficacy of spironolactone with placebo, doxazosin, and bisoprolol showed superiority of spironolactone in blood pressure lowering in patients with resistant hypertension. Thus, revised ACC/AHA and ESC/ESH guideline for arterial hypertension recommended spironolactone as the fourth agent for resistant hypertension. However, in real world, adherence to spironolactone may not be adequate because of adverse effect such as gynecomastia, hyperkalemia, and so on.
Recently, sub-study of PATHWAY-2 revealed that amiloride changes systolic blood pressure by -22.2 mmHg (95% CI, -24.7 to -19.7) which is comparable with the effect of spironolactone (-21.8 mmHg; 95% CI, -24.2 to -19.3). However, it was not randomized clinical trial to compare the effect between spironolactone and amiloride in patients with resistant hypertension.
This study aims to compare the effect of spironolactone and amiloride on home blood pressure in resistant hypertensive patients and to compare the rate of target blood pressure achievement between spironolactone and amiloride in resistant hypertensive patients.

Start Date16 Nov 2020

Sponsor / Collaborator

Yonsei University

100 Clinical Results associated with Amiloride Hydrochloride

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100 Translational Medicine associated with Amiloride Hydrochloride

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100 Patents (Medical) associated with Amiloride Hydrochloride

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7,957

Literatures (Medical) associated with Amiloride Hydrochloride

01 Feb 2025·Journal of Advanced Research

Collecting duct NCOR1 controls blood pressure by regulating mineralocorticoid receptor

Article

Author: Duan, Sheng-Zhong ; Hou, Chen-Chen ; Hao, Chuan-Ming ; Bai, Lan ; Shang, Da ; Zhang, Xing-Yu ; Du, Lin-Juan ; Sun, Ke ; Wang, Yong-Li

INTRODUCTIONNuclear receptor corepressor 1(NCOR1) is reported to play crucial roles in cardiovascular diseases, but its function in the kidney has remained obscure.OBJECTIVEWe aim to elucidate the role of collecting duct NCOR1 in blood pressure (BP) regulation.METHODS AND RESULTSCollecting duct NCOR1 knockout (KO) mice manifested increased BP and aggravated vascular and renal injury in an angiotensin II (Ang II)-induced hypertensive model. KO mice also showed significantly higher BP than littermate control (LC) mice in deoxycorticosterone acetate (DOCA)-salt model. Further study showed that collecting duct NCOR1 deficiency aggravated volume and sodium retention after saline challenge. Among the sodium transporter in the collecting duct, the expression of the three epithelial sodium channel (ENaC) subunits was markedly increased in the renal medulla of KO mice. Consistently, BP in Ang II-infused KO mice decreased significantly to the similar level as those in LC mice after amiloride treatment. ChIP analysis revealed that NCOR1 deficiency increased the enrichment of mineralocorticoid receptor (MR) on the promoters of the three ENaC genes in primary inner medulla collecting duct (IMCD) cells. Co-IP results showed interaction between NCOR1 and MR, and luciferase reporter results demonstrated that NCOR1 inhibited the transcriptional activity of MR. Knockdown of MR eliminated the increased ENaC expression in primary IMCD cells isolated from KO mice. Finally, BP was significantly decreased in Ang II-infused KO mice after treatment of MR antagonist spironolactone and the difference between LC and KO mice was abolished.CONCLUSIONSNCOR1 interacts with MR to control ENaC activity in the collecting duct and to regulate sodium reabsorption and ultimately BP. Targeting NCOR1 might be a promising tactic to interrupt the volume and sodium retention of the collecting duct in hypertension.

11 Dec 2024·Science Translational Medicine

Repurposing an epithelial sodium channel inhibitor as a therapy for murine and human skin inflammation

Article

Author: Szafran, Rebecca ; Jackrazi, Leandra V. ; Guo, Konnie Q. ; Ramanathan, Muthukumar ; Butte, Atul J. ; Nguyen, Ngon T. ; Gurevich, Irina ; Fuhriman, Jessica M. ; Inayathullah, Mohammed ; Marinkovich, M. Peter ; Winge, Mårten C. G. ; Siprashvili, Zurab ; Porter, Douglas F. ; Nasrallah, Mazen ; Khavari, Paul A. ; Rajadas, Jayakumar

Inflammatory skin disease is characterized by a pathologic interplay between skin cells and immunocytes and can result in disfiguring cutaneous lesions and systemic inflammation. Immunosuppression is commonly used to target the inflammatory component; however, these drugs are often expensive and associated with side effects. To identify previously unidentified targets, we carried out a nonbiased informatics screen to identify drug compounds with an inverse transcriptional signature to keratinocyte inflammatory signals. Using psoriasis, a prototypic inflammatory skin disease, as a model, we used pharmacologic, transcriptomic, and proteomic characterization to find that benzamil, the benzyl derivative of the US Food and Drug Administration–approved diuretic amiloride, effectively reversed keratinocyte-driven inflammatory signaling. Through three independent mouse models of skin inflammation (Rac1 G12V transgenic mice, topical imiquimod, and human skin xenografts from patients with psoriasis), we found that benzamil disrupted pathogenic interactions between the small GTPase Rac1 and its adaptor NCK1. This reduced STAT3 and NF-κB signaling and downstream cytokine production in keratinocytes. Genetic knockdown of sodium channels or pharmacological inhibition by benzamil prevented excess Rac1-NCK1 binding and limited proinflammatory signaling pathway activation in patient-derived keratinocytes without systemic immunosuppression. Both systemic and topical applications of benzamil were efficacious, suggesting that it may be a potential therapeutic avenue for treating skin inflammation.

01 Dec 2024·American Journal of Physiology-Renal Physiology

5/6 Nephrectomy impairs acute kaliuretic responses and predisposes to postprandial hyperkalemia

Article

Author: Imenez Silva, Pedro Henrique ; Rotmans, Joris I. ; de Borst, Martin H. ; Vogt, Liffert ; Danser, A. H. Jan ; Wei, Kuang-Yu ; Hoorn, Ewout J. ; Gritter, Martin

Rats who underwent 5/6 nephrectomy demonstrate a reduced ability to excrete an acute K+ load with the development of postprandial hyperkalemia. 5/6 Nephrectomy attenuates K+-induced natriuresis and impairs ENaC regulation despite intact NCC dephosphorylation and increased plasma aldosterone. This offers a potential explanation for why patients with chronic kidney disease are predisposed to postprandial hyperkalemia.

100 Deals associated with Amiloride Hydrochloride

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External Link

KEGG	Wiki	ATC	Drug Bank
D00649	Amiloride Hydrochloride	C03DB01	DB00594

R&D Status

10 top approved records.

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Indication	Country/Location	Organization	Date
Heart Failure	US	Padagis US LLC	05 Oct 1981
Hypertension	US	Padagis US LLC	05 Oct 1981

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05079789 (AMILOR, CTgov)	Phase 3	Hypernatremia \| Edema \| Nephrotic Syndrome	20	Amiloride (Amiloride)	omjyxormyj(qqigtlahju) = efabnelvxr zdkrgrtyky (edtkjauqvt, mvojfmlewj - tcgeyrajcf) View more	-	14 Jan 2025
				Furosemide (Furosemide)	omjyxormyj(qqigtlahju) = psjgcktwzt zdkrgrtyky (edtkjauqvt, jhkysqnhne - xmorgcayax) View more
PMON89 (ENDO2022)	Not Applicable	Diabetes Insipidus, Nephrogenic	-	Temozolomide	fhlcpfazna(rdneqhhvvp) = jqeqxflthe nbasfmodaz (wyyucdruqx, 280 - 295) View more	-	01 Nov 2022
				Pantoprazole	mlupnhmlyg(inrnxxpoxr) = txwzikcnwf wxsjvzaozu (pegoefsiso )
NCT02522650 (Pubmed \| Am J Nephrol)	Phase 4	Kidney Diseases	12	Amiloride 5 mg	ssstvzcdaf(lueyqmcfnk) = bnevxgiuef rxyosquqwb (oyuntjfgbb )	-	06 May 2021
				Triamterene 50 mg	ssstvzcdaf(lueyqmcfnk) = dsctyrsojr rxyosquqwb (oyuntjfgbb )
ESH2021	Not Applicable	Acute Kidney Injury plasmin activity	-	Amiloride (Normal salt diet (NS))	(nesvhscfdx) = cvxjodnxur kkzylprljx (afsucnojfj ) View more	Positive	01 Apr 2021
				Amiloride (Aldosterone + high salt diet (Ald+HS))	(nesvhscfdx) = ecpqxamdta kkzylprljx (afsucnojfj ) View more
ASN2020	Not Applicable	Kidney Diseases	12	Amiloride 5 mg	(nfvwyltltf) = Three patients exited the study due to hyperkalemia knwvdarbfp (npbimtoaqo )	Positive	19 Oct 2020
				Triamterene 50 mg
ASN2020	Not Applicable	Urolithiasis	31	Amiloride	(ncnzzshhro) = Three (20%) patients stopped due to delayed intolerance and 2 (13%) due to elevated urinary calcium fhriqpdtgb (wabxazdwty ) View more	Negative	19 Oct 2020
				Thiazide
NCT01733680 (CTgov)	Early Phase 1	Attention Deficit Disorder With Hyperactivity	3	Behavioral+amiloride (Amiloride)	rboncsclhr(vtzvuuinym) = wsfoksjfxo voypxbcldr (isfjnbefka, dnxpmhdahr - yamidoojfk) View more	-	20 Jul 2018
				Behavioral (Placebo)	rboncsclhr(vtzvuuinym) = lcmpapcvxt voypxbcldr (isfjnbefka, euxqdbzvtw - ahmcikhbms) View more
ESC2016	Not Applicable	Coronary Disease	-	Amiloride HCl Dihydrate	xkcxldnjxu(trtewnxosm) = reiayodjgu dclpbbbdfe (ddhmjpgdrn )	-	30 Aug 2016
ASN2015	Not Applicable	Hypokalemia \| Gitelman Syndrome SLC12A3 gene	-	Spironolactone	ximuxeaokr(lbiddnlawl) = ndydxzerpn vxryixssss (ydjqgygoyz ) View more	Positive	03 Nov 2015
				Amiloride	ximuxeaokr(lbiddnlawl) = qscuiyrwkn vxryixssss (ydjqgygoyz ) View more
SP309 (ERA2015)	Not Applicable	Kidney Diseases urine albumin-to-creatinine ratio (ACR)	21	Spironolactone	xqjndoiwob(ufadqgmwry) = vtvlyrjyhv cszpwgmbgl (twwjouiajg, -21% - -47.9%)	Positive	21 May 2015
				Hydrochlorothiazide	xqjndoiwob(ufadqgmwry) = zfewqdpwvg cszpwgmbgl (twwjouiajg, -28.1% - -56.9%)