Discovery of (2S,4R)-1-(2-Aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic Acid Hydrochloride (GAP-134)13, an Orally Active Small Molecule Gap-Junction Modifier for the Treatment of Atrial Fibrillation

Butera, John; Larsen, Bjarne Due; Hennan, James K.; Kerns, Edward H.; Di, Li; Alimardanov, Asaf; Swillo, Robert E.; Morgan, Gwen A.; Liu, Kun; Wang, Qiang; Rossman, Eric I.; Unwalla, Rayomand J.; McDonald, Leonard A.; Huselton, Christine; Petersen, Jørgen S.

doi:10.1021/jm801558d

Cited by 35 publications

(29 citation statements)

References 18 publications

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“…In contrast with AAP10, danegaptide decreased the dye uptake in C6 cells stably transfected with Cx43 [108]. Hence this compound may display favorable effects both at the level of gap junctions, as well as at the level of hemichannels [110].…”

Section: Rotigaptide (Zp123 Gap-486)mentioning

confidence: 91%

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Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias

Magyar

Bányász

Szentandrássy

et al. 2014

CPD

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The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling.Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR.Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.

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Section: Rotigaptide (Zp123 Gap-486)mentioning

confidence: 91%

“…GAP134 has beneficial effects. Namely GAP134 promotes intercellular coupling, enhances the conduction velocity, and simultaneously limits the cellular ATP release through hemichannels [110].…”

Section: The Possible Antiarrhythmic Effects Of Gap Junction Modulatorsmentioning

confidence: 99%

Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias

Magyar

Bányász

Szentandrássy

et al. 2014

CPD

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“…In this regard, we recently identified the first, orally available, gap junction modifier, GAP-134, which is a dipeptide chemically derived from the class of antiarrhythmic peptides such as rotigaptide (also called ZP123) (Butera et al, 2009). GAP-134 dose-dependently reduced calcein dye uptake in C6 cells overexpressing Cx43 and prolonged time to cardiac conduction block in a mouse model of calcium overload (Butera et al, 2009).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…GAP-134 dose-dependently reduced calcein dye uptake in C6 cells overexpressing Cx43 and prolonged time to cardiac conduction block in a mouse model of calcium overload (Butera et al, 2009). In Butera et al (2009), the efficacy and potency of GAP-134 were directly compared with rotigaptide and found to be similar. In the present study, we add additional knowledge regarding the mechanism of action of GAP-134 by investigating its action on conduction velocity before and after metabolic stress, using rat atrial muscle strips.…”

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The Gap Junction Modifier, GAP-134 [(2S,4R)-1-(2-Aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic Acid], Improves Conduction and Reduces Atrial Fibrillation/Flutter in the Canine Sterile Pericarditis Model

Rossman¹,

Liu²,

Morgan³

et al. 2009

J Pharmacol Exp Ther

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Gap junction uncoupling can alter conduction pathways and promote cardiac re-entry mechanisms that potentiate many supraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL). Our objective was to determine whether GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], a small dipeptide gap junction modifier, can improve conduction and ultimately prevent AF/AFL. In rat atrial strips subjected to metabolic stress, GAP-134 prevented significantly conduction velocity slowing at 10 nM compared with vehicle (p Ͻ 0.01). In the canine sterile pericarditis model, conduction time (CT; n ϭ 5), atrial effective refractory period (AERP; n ϭ 3), and AF/AFL duration/inducibility (n ϭ 16) were measured 2 to 3 days postoperatively in conscious dogs. CT was significantly faster after GAP-134 infusion (average plasma concentration, 250 nM) at cycle lengths of 300 ms (66.2 Ϯ 1.0 versus 62.0 Ϯ 1.0 ms; p Ͻ 0.001) and 200 ms (64.4 Ϯ 0.9 versus 61.0 Ϯ 1.3 ms; p Ͻ 0.001). No significant changes in AERP were noted after GAP-134 infusion. The mean number of AF/AFL inductions per animal was significantly decreased after GAP-134 infusion (2.7 Ϯ 0.6 versus 1.6 Ϯ 0.8; p Ͻ 0.01), with total AF/AFL burden being decreased from 12,280 to 6063 s. Western blot experiments showed no change in connexin 43 expression. At concentrations exceeding those described in the AF/AFL experiments, GAP-134 had no effect on heart rate, blood pressure, or any electrocardiogram parameters. In conclusion, GAP-134 shows consistent efficacy on measures of conduction and AF/AFL inducibility in the canine sterile pericarditis model. These findings, along with its oral bioavailability, underscore its potential antiarrhythmic efficacy.

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Matrix‐assisted laser desorption/ionization imaging mass spectrometry of intraperitoneally injected danegaptide (ZP1609) for treatment of stroke‐reperfusion injury in mice

Wang

Freitas‐Andrade

Bechberger

et al. 2018

Rapid Comm Mass Spectrometry

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Discovery of (2S,4R)-1-(2-Aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic Acid Hydrochloride (GAP-134)¹³, an Orally Active Small Molecule Gap-Junction Modifier for the Treatment of Atrial Fibrillation

Cited by 35 publications

References 18 publications

Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias

Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias

The Gap Junction Modifier, GAP-134 [(2S,4R)-1-(2-Aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic Acid], Improves Conduction and Reduces Atrial Fibrillation/Flutter in the Canine Sterile Pericarditis Model

Matrix‐assisted laser desorption/ionization imaging mass spectrometry of intraperitoneally injected danegaptide (ZP1609) for treatment of stroke‐reperfusion injury in mice

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