Delving into the Latest Updates on Ivabradine extended release(Abbott Laboratories) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Ivabradine

Target

HCN channels

Action

blockers

Mechanism

HCN channels blockers(Hyperpolarization-activated cyclic nucleotide-gated channel blockers)

Therapeutic Areas

Cardiovascular DiseasesNervous System Diseases

Active Indication

Heart FailureAngina Pectoris

Inactive Indication-

Originator Organization

Abbott Laboratories

Active Organization

Abbott Laboratories

Inactive Organization-

Drug Highest PhasePhase 3

First Approval Date-

RegulationOrphan Drug (United States)

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Structure/Sequence

Molecular FormulaC27H36N2O5

InChIKeyACRHBAYQBXXRTO-OAQYLSRUSA-N

CAS Registry155974-00-8

AbstractCardiac alternans (C‐ALT) is a phenomenon of alternating strong and weak contractions in the heart and is considered a risk factor for the development of heart failure and arrhythmias. However, no model has been reported that can induce C‐ALT in vitro using human cells, and the developmental mechanism of C‐ALT has not been studied using human cells. In this study, we successfully induced C‐ALT in vitro using human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs). By stimulating β‐adrenergic receptor with isoproterenol on hiPSC‐CMs cultured in atmospheric condition (with ~0.04% CO2), contractility and calcium transient were observed to alternately increase and decrease with each beat. In contrast, C‐ALT was not induced in hiPSC‐CMs cultured at 5% CO2 concentration. Since previous studies have linked C‐ALT to problems with calcium regulation in the sarcoplasmic reticulum (SR), we exposed hiPSC‐CMs to compounds that alter SR Ca2+ loading and analyzed their contractile responses. The results showed that exposure to verapamil, thapsigargin, and ryanodine either suppressed or eliminated C‐ALT. In contrast, omecamtiv mecarbil and blebbistatin, which alter contractility without SR Ca2+ loading, did not induce or suppress C‐ALT. These results suggest that C‐ALT in hiPSC‐CMs induced by isoproterenol may be due to abnormal regulation of the ryanodine receptor's opening and closing caused by excessive Ca2+ load in the SR from β‐adrenergic receptor stimulation.

01 Nov 2024·Journal of Computational Biophysics and Chemistry

Molecular Docking, Quantum Mechanics and Molecular Dynamics Simulation of Anti-CAD Drugs Against High-Risk Xanthine Dehydrogenase Variants Associated with Oxidative Stress Pathways

Author: Ahmed, Shiek S. S. J. ; Ahmad, Sheikh F. ; Emran, Talha Bin ; Janakiraman, V. ; Attia, Sabry M. ; Sudhan, M.

Xanthine dehydrogenase (XDH) contributes significantly to generating reactive oxygen species in coronary artery disease (CAD). XDH has been proposed as a therapeutic target, but its genetic variants could affect protein structure and drug response. We aimed to assess protein structure modification occur due to genetic variants and to screen 215 CAD drugs for their utility in personalized CAD treatment against the XDH variants. A series of computational methods were implemented to identify pathogenic variants that cause XDH structure instability localized at the con served regions contributing to functional significance. Then, the XDH structures with the pathogenic variants were modeled using two different approaches to select the best models for docking with the CAD drugs. Finally, the stability of the docked complexes and their ability to transfer electrons were evaluated using molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculation. Among 751 variants examined; R149C and Q919R showed high pathogenicity, localized in conserved regions could alter protein structure and function. Further, docking of CAD drugs against XDH (native, R149C and Q919R) showed vericiguat with higher affinity, ranging from −7.95 kcal/mol to −10.41 kcal/mol, than the well-known XDH inhibitor (febuxostat, −5.73 kcal/mol to −8.35 kcal/mol). This indicates that vericiguat will be effective in CAD treatment, regardless of the XDH variants. Additionally, MD simulation and QM/MM confirmed vericiguat stability and electron transfer ability to form hydrogen bonds with the XDH protein. In conclusion, vericiguat will be beneficial for the personalized treatment of CAD by inhibiting XDH variants. Additional clinical studies are necessary to confirm our findings.

01 Nov 2024·Journal of Biological Chemistry

Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine

Article

Author: Zhang, Yuting ; Li, Jian ; Cheng, Xinyu ; Xiong, Bing ; Zhang, Minqing ; Nan, Weiwei ; Zhang, Wei ; Wan, Shuangyan ; Zhang, Jin ; Che, Tong ; Zeng, Bo ; Lv, Sijia ; Yang, Tingting

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a crucial role in regulating neuronal excitability. Despite growing evidence supporting the therapeutic potential of HCN1 inhibition in treating neurological disorders, the structural basis of channel inhibition by inhibitor has remained elusive. Here, we present the cryo-electron microscopy structure of human HCN1 channel in complex with inhibitor ivabradine, the drug on the market that acts on HCN channels. Combining electrophysiology, mutagenesis, and molecular dynamics simulations, our findings reveal that ivabradine binds to a previously unidentified pocket formed between the S4, S1, and HCN domain. Furthermore, through structure-based virtual screening, we identify two Food and Drug Administration-approved drugs that can inhibit the HCN1 channel by interacting with the ivabradine-binding site. Our results not only provide insights into the structural intricacies of ivabradine-mediated inhibition, but also offer a potential pharmacological framework for developing novel drugs targeting the HCN1 channel. The elucidation of these molecular interactions serves as a foundational step in advancing therapeutic strategies for modulating HCN1 activity, contributing to the broader landscape of drug discovery and development in this area.

100 Deals associated with Ivabradine extended release(Abbott Laboratories)

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Ivabradine extended release(Abbott Laboratories)	C01EB17	DB09083

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	Phase 3	-	Abbott Laboratories	-
Angina Pectoris	Phase 1	-	Abbott Laboratories	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04436016 (Pubmed)	Phase 4	high-sensitive cardiac troponin T elevation	78	Ivabradine 2.5 mg	gqyxvoyarj(vndrnkbegd) = rslhdqorhi qxcfshtiih (rlrorgbjdt ) View more	Positive	01 Jul 2024
				Ivabradine 5.0 mg	gqyxvoyarj(vndrnkbegd) = gvdtsmmzjc qxcfshtiih (rlrorgbjdt ) View more
ESC2023	Not Applicable	Chronic heart failure	98	HRR strategy using Ivabradine	(tkeidiyckz) = smguafzlzo qixayveqlh (wufbwkgnvm ) View more	Positive	21 May 2023
				Ivabradine	(tkeidiyckz) = eulpabmhgu qixayveqlh (wufbwkgnvm ) View more
ESC2023	Not Applicable	Heart failure with normal ejection fraction Add-on	-	Ivabradine	pbjpvmnvxv(xsjxmzpvif): RR = 0.84 (95% CI, 0.67 - 1.04) View more	-	21 May 2023
				Non-Ivabradine treatments
NCT03137537 (CTgov)	Phase 2	Primary Dysautonomias \| Lymphoma	23	Ivabradine (Ivabradine)	hljeobgcof(aughbijvof) = gmaldpwtdp rmvtnscerz (aupbbuyyws, jthizicgtx - tniabsskhs) View more	-	10 Feb 2022
				Placebo Oral Tablet (Placebo Oral Tablet)	hljeobgcof(aughbijvof) = znqrhszakz rmvtnscerz (aupbbuyyws, burdjntjyc - xsztdjpqpe) View more
ESC2021	Not Applicable	Heart Failure	256	Ivabradine	(ztdovyssem) = euthczjftb ydisyqqmtj (coprdxgljk ) View more	-	29 Jun 2021
POSITIVE study (ESC2021)	Not Applicable	Chronic heart failure	1,003	Ivabradine	(kcqeozugma) = tquguhvpqu wlqkcjityl (eekfsgznya )	Positive	29 Jun 2021
ESC2020	Not Applicable	Angina, Unstable	23	Ivabradine	qupafoglmz(avvshiltaz) = hshxwuvuwv xxeomghnof (isabzasuqc ) View more	-	28 Aug 2020
				Placebo	(vgkxpussms) = oyarqnkxpf qidziviwtk (hichlqmibw ) View more
NCT03456856 (CTgov)	Phase 4	Heart Failure \| Left ventricular systolic dysfunction	30	Ivabradine	oziwncxnhq(wqbryrmdsx) = vihgxfopsk icmtyqqeup (usdsnnycfh, rtfszvugww - bqxhyunsjk) View more	-	07 Apr 2020
ESC2019	Not Applicable	Heart Failure	20	Ivabradine	ihyxjpsepl(wzmnedrlqt) = nmiraglihn ifkbplpidc (vclczhsoxs )	Positive	28 May 2019
				Dobutamine+Ivabradine	ihyxjpsepl(wzmnedrlqt) = daxnupmnkc ifkbplpidc (vclczhsoxs )
SHIfT (ESC2019)	Not Applicable	Heart failure with reduced ejection fraction	411	Ivabradine	(ueskcowswi) = yefzvzqqyx hgfyhacizx (mwlbdfszjt ) View more	-	27 May 2019
				Placebo	(ueskcowswi) = itnnydwoio hgfyhacizx (mwlbdfszjt ) View more