Potent, acid-stable and orally active macrolide-type motilin receptor agonists, GM-611 and the derivatives

Koga, Hiroshi; Sato, Tsutomu; Tsuzuki, Koichi; Onoda, Harumi; Kuboniwa, Hitoshi; Takanashi, Hisanori

doi:10.1016/s0960-894x(01)80359-0

Cited by 38 publications

(39 citation statements)

References 12 publications

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“…Further efforts to eliminate the antimicrobial activity as well as enhance the motilin-like activities produced a large number of derivatives such as EM-523 [5] , EM-574 [6] , ABT-229 [7] and others [8] in the hope of ameliorating the motility disorders in patients with idiopathic, diabetic, postoperative or chemotherapy-induced gastroparesis. Unfortunately, most of EMA derivatives rapidly degrade in acidic pH as in the stomach [9] . 1 ) has been synthesized in an attempt to improve acid stability.…”

Section: Introductionmentioning

confidence: 99%

“…In this new derivative, internal ketalization of the 12-hydroxy group of EMA, which occurs under acidic conditions, is protected by 12-O -methylation, so that the acidic stability is greatly increased. Furthermore, small sophisticated modifications in other side chains have conferred enhanced motilin activity, making mitemcinal promising as an orally administrable prokinetic agent [9] . Accordingly, mitemcinal was created to develop the first acid-resistant non-peptide motilin agonist, with high prokinetic activity but devoid of antibacterial activity.…”

Section: Introductionmentioning

confidence: 99%

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In vitro Pharmacological Characterization of Mitemcinal (GM-611), the First Acid-Resistant Non-Peptide Motilin Receptor Agonist, in Smooth Muscle of Rabbit Small Intestine

Takanashi¹,

Koga²,

Ōmura³

2006

Pharmacology

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The pharmacological properties of mitemcinal (GM-611), the first acid-resistant non-peptide motilin agonist, were investigated in the smooth muscle of the rabbit small intestine and compared with porcine motilin (pMTL), erythromycin A (EMA) and its derivatives (EM-523, EM-574 and ABT-229). Mitemcinal, pMTL, EMA, EM-523, EM-574 and ABT-229 produced concentration-dependent contractions with approximately the same maximum contractions in the isolated rabbit duodenum longitudinal strips. The contractile response to mitemcinal or pMTL was competitively inhibited by a selective motilin antagonist, GM-109. The pA₂ values for GM-109 as an antagonist of mitemcinal and pMTL showed approximately the same values. However, the concentration-dependent contractile responses to mitemcinal or pMTL were not affected by pretreatment with atropine, tetrodotoxin, hexamethonium, naloxone or tropisetron. The removal of calcium ions from the medium and pretreatment with verapamil greatly suppressed the contractions induced by mitemcinal and pMTL. The contractile response to mitemcinal was not affected by preincubation in acidic solutions, while those of EM-523, EM-574 and ABT-229 were strongly diminished in the same condition. Mitemcinal as well as other motilin agonists displaced ¹²⁵I-pMTL bound to a homogenate of the rabbit duodenum muscle tissue. The displacement curves of all these compounds were parallel. These results indicate that mitemcinal is a selective and full motilin receptor agonist in the smooth muscle of the rabbit small intestine and that this agent has an excellent acid-resistant property.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In vitro Pharmacological Characterization of Mitemcinal (GM-611), the First Acid-Resistant Non-Peptide Motilin Receptor Agonist, in Smooth Muscle of Rabbit Small Intestine

Takanashi¹,

Koga²,

Ōmura³

2006

Pharmacology

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“…Clinical trials of mitemcinal in patients with diabetic gastroparesis are currently underway (McCallum et al, 2007). Here, an extended series of safety pharmacology protocols and evaluations of mitemcinal, which was synthesized in our organic chemistry laboratories (Koga et al, 1994), have been undertaken to assess the potential risk in clinical use. In our studies, cisapride was used as a reference compound because it markedly prolongs QT interval at therapeutic dose, and cases of TdP induced by cisapride are frequently compared with erythromycin.…”

Section: Discussionmentioning

confidence: 99%

“…1.; Koga et al, 1994). Mitemcinal has shown potent gastrointestinal motility-stimulating activity via motilin receptors in rabbits, dogs and monkeys Ozaki et al, 2007;Yogo et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Electrophysiology Assays of Mitemcinal (Gm-611), a Novel Prokinetic Agent Derived From Erythromycin

et al. 2007

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-Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. Erythromycin has shown QT prolongation and torsades de pointes (TdP) in humans and cisapride, a second class of prokinetic agents typified by the 5-HT 4 receptor agonist, has been terminated due to TdP. In this study an extended series of safety pharmacology protocols and evaluations have been undertaken to assess the potential risk of mitemcinal on QT prolongation or proarrhythmic effects. Mitemcinal and its metabolites, GM-577 and GM-625, inhibited the human ether-a-go-gorelated gene (HERG) tail current in a concentration-dependent manner with IC 50 values of 20.2, 41.7, and 55.0 μM, respectively. Administration of 10 mg/kg mitemcinal in anesthetized guinea pigs resulted in a slight prolongation of the monophasic action potential (MAP) duration during atrial pacing at the plasma concentration of mitemcinal 1.1 μM, with low maximum increases in MAPD 70 (6.6%) and MAPD 90 (4.6%) relative to vehicle. A 10-min infusion of 20 mg/kg of mitemcinal in a proarrhythmic rabbit model did not evoke TdP even when QT and corrected QT (QTc) intervals were significantly prolonged. In this study, the Cmax plasma-free concentration of mitemcinal indicates that the prolongation was more than 400-fold that of the therapeutic dose. Our findings of a wide safety margin and the absence of TdP within this margin suggest that mitemcinal may provide sufficient safety in clinical use.

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“…Mitemcinal([2S,4R,5R,8R,9S,10S,11R,12R]-9-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-Hexopyranosyl)oxy]-5-ethyl-4-methoxy-2, 4,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(isopropyl-methylamino)-β-D-xylo-hexopyranosyl]oxy]-6,15-dioxabicyclo[10.2.1]pentadec-14(1)-ene-3,7-dione(E)-2-butenedioic acid salt (2:1), Code name: GM-611) is an orally active erythromycin derivative without antibacterial activity (Koga et al, 1994). Mitemcinal has shown potent gastrointestinal motility-stimulating activity via motilin receptors in rabbits, dogs and monkeys Ozaki et al, 2007;.…”

Section: Introductionmentioning

confidence: 99%

Hemodynamic and Electrophysiological Effects of Mitemcinal (Gm-611), a Novel Prokinetic Agent Derived From Erythromycin in a Halothane-Anesthetized Canine Model

et al. 2007

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-Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. We investigated the QT-prolonging effects of mitemcinal using a halothane-anesthetized canine model. Intravenous administration of mitemcinal at doses of more than 8.3 mg/ kg per 10 min significantly prolonged the QT interval corrected by Fridericia's corrections. Mitemcinal exhibited a bradycardiac effect and produced significantly greater prolongation in monophasic action potential duration (MAP 90 ) at sinus rhythm compared with MAP 90 at pacing and showed reverse usedependent prolongation of repolarization, suggesting that the negative chronotropic effect of mitemcinal potentiates the prolongation of the repolarization period. A technique using MAP/pacing electrodes allowed measurements of both MAP 90 and effective refractory period (ERP) simultaneously at the same ventricular site. Although mitemcinal slightly prolonged the MAP 90(CL400) and ERP in comparison with the control group at the dose of 25 mg/kg per 10 min, the terminal repolarization period, the difference between MAP 90(CL400) and ERP, did not increase suggesting the absence of a proarrhythmic effect even with a 7000-fold for the therapeutic blood concentration as free level. The electrophysiological results from mitemcinal in this study indicate that the risk of serious arrhythmia such as torsades de pointes, a major clinical concern related to QT interval prolongation, might be low.

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Potent, acid-stable and orally active macrolide-type motilin receptor agonists, GM-611 and the derivatives

Cited by 38 publications

References 12 publications

In vitro Pharmacological Characterization of Mitemcinal (GM-611), the First Acid-Resistant Non-Peptide Motilin Receptor Agonist, in Smooth Muscle of Rabbit Small Intestine

In vitro Pharmacological Characterization of Mitemcinal (GM-611), the First Acid-Resistant Non-Peptide Motilin Receptor Agonist, in Smooth Muscle of Rabbit Small Intestine

Preclinical Electrophysiology Assays of Mitemcinal (Gm-611), a Novel Prokinetic Agent Derived From Erythromycin

Hemodynamic and Electrophysiological Effects of Mitemcinal (Gm-611), a Novel Prokinetic Agent Derived From Erythromycin in a Halothane-Anesthetized Canine Model

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