Ken-ichi Ozaki

Chugai pharmceutical, Japan

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Publications (16)43.68 Total impact

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    ABSTRACT: We successfully discovered peptidomimetic motilin antagonists (17c and 17d) through the improvement of physicochemical properties of a tetrapeptide antagonist (2). Furthermore, with oral administration and based on motilin antagonistic activity, both compounds suppressed motilin-induced colonic and gastric motility in conscious dogs.
    Bioorganic & medicinal chemistry letters 08/2009; 19(13):3426-9. · 2.65 Impact Factor
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    ABSTRACT: The pharmacological properties of MA-2029, a selective and competitive motilin receptor antagonist, were investigated in conscious dogs after oral administration. Gastrointestinal contractile activity was recorded by chronically implanted force transducers. The proximal gastric volume was measured with a barostat under constant pressure. Gastric emptying was examined using the paracetamol absorption test. MA-2029 (0.3-10 mg/kg, p.o.) administered in the interdigestive state inhibited gastrointestinal contractions induced by motilin (3 microg/kg, i.v.) in a dose-dependent manner. MA-2029 (0.3-3 mg/kg, p.o.) also inhibited the occurrence of spontaneous phase III contractions, even though MA-2029 had no effect on basal gastrointestinal motility or basal gastric emptying even at 10 and 30 mg/kg p.o. The inhibitory effect of MA-2029 on motilin-induced gastrointestinal motility corresponded to its plasma concentration. Motilin (0.3 microg/kg/h, i.v. infusion) reduced the proximal gastric volume by about 50% of control during isobaric distension. This effect was also inhibited by MA-2029 (1-10 mg/kg, p.o.) in a dose-dependent manner. In the digestive state, injection of motilin (3 microg/kg, i.v.) induced diarrhea in 9 of 11 dogs. MA-2029 (1-30 mg/kg, p.o.) reduced the incidence of diarrhea induced by motilin in a dose-dependent manner. The results indicate that MA-2029 inhibits hypermotility induced by motilin in conscious dogs without having an effect on the basal gastrointestinal tone or gastric emptying rate. MA-2029 may be useful in treating gastrointestinal disorders in which the pathogenesis involves the elevation of circulating motilin.
    European journal of pharmacology 06/2009; 615(1-3):185-92. · 2.59 Impact Factor
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    ABSTRACT: 1. The aim of the present study was to evaluate the effects of mitemcinal (GM-611), an orally active motilin receptor agonist, on delayed gastric emptying in a canine model of diabetic gastroparesis and to compare these effects with those of cisapride. 2. Moderate hyperglycaemia was induced by a single intravenous injection of a mixture of streptozotocin (30 mg/kg) and alloxan (50 mg/kg). Dogs that maintained moderate hyperglycaemia (fasting plasma glucose 200-300 mg/dL) without insulin treatment were selected and gastric emptying in these dogs was determined by the paracetamol method. 3. One year after the onset of diabetes, there was no difference in the gastric emptying of normal and diabetic dogs. However, after 5 years, the diabetic dogs showed delayed gastric emptying. The motor nerve conduction velocity of the tibial nerve was significantly lower in diabetic dogs compared with normal dogs at both time points. 4. Histopathological examination at the end of the study showed that there were fewer nerve fibres in both dorsal vagal and tibial nerves of diabetic dogs compared with normal dogs. The onset of delayed gastric emptying is thought to have occurred gradually, in parallel with abnormal autonomic nerve function induced by the long period of moderate hyperglycaemia. 5. Oral administration of mitemcinal (0.125, 0.25 or 0.5 mg/kg) dose-dependently accelerated delayed gastric emptying, significant at 0.5 mg/kg, in diabetic dogs, whereas cisapride (1, 3 or 10 mg/kg) had no significant effect. These results add to the existing evidence that mitemcinal is likely to be useful for treating diabetic gastroparesis.
    Clinical and Experimental Pharmacology and Physiology 08/2008; 35(7):788-96. · 2.41 Impact Factor
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    ABSTRACT: We assessed and compared the effects of oral mitemcinal (an orally active, erythromycin-derived motilin-receptor agonist; Code name: GM-611), erythromycin, EM-574 and cisapride on gastric emptying in conscious Rhesus monkeys using the acetaminophen method. Mitemcinal and erythromycin induced significant, dose-dependent increases in indices of gastric emptying, but mitemcinal required a much lower dose for the same effect. Cisapride induced a bell-shaped dose response, and EM-574, a potent erythromycin derivative and originally developed as an enteric coated formulation, had little effect when it was given orally uncoated. Since our previous study showed that response to motilin is similar in Rhesus monkeys and humans, these results suggest that oral mitemcinal may be effective for the treatment of symptoms in human disorders related to delayed gastric emptying (e.g., functional dyspepsia and gastroparesis). Combined with the results of other studies, these results suggest that mitemcinal may be able to replace the withdrawn drug, cisapride, as the drug of choice for treating delayed gastric emptying.
    Digestive Diseases and Sciences 05/2008; 53(4):912-8. · 2.26 Impact Factor
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    ABSTRACT: This study was conducted to evaluate the suitability of a new minipig model for investigating aspects of diabetes such as delayed gastric emptying and glucose metabolism abnormalities, and to test the effects of mitemcinal (GM-611), an orally active erythromycin-derived motilin receptor agonist, on gastric emptying and postprandial glucose in normal and diabetic minipigs. Intravenous injection of 300 mg/kg streptozotocin (STZ) to 5-week-old minipigs induced moderate hyperglycemia (about 200 mg/dl) for >80 weeks without insulin treatment. Decreased insulin production (P<.05), increased area under the glucose curve (P<.05), and slower glucose disappearance (P<.05) were demonstrated, and there was no severe inhibition of body weight gain, liver failure, or renal failure. Gastric emptying was significantly delayed in diabetic minipigs (P<.05) at 80 weeks, but not at 40 weeks, post-STZ. Oral administration of mitemcinal (5 mg/kg) at 80 weeks accelerated gastric emptying and induced a similar postprandial glucose profile in normal and diabetic minipigs with delayed gastric emptying. The new diabetic minipig model showed suitability for investigating diabetes, gastric emptying, and plasma glucose excursions. Since delayed gastric emptying and irregular plasma glucose excursions are characteristic of diabetic gastroparesis, the accelerating and regulating effects of mitemcinal on this model add to the existing evidence that mitemcinal is likely to be useful for treating diabetic gastroparesis.
    Journal of diabetes and its complications 05/2008; 22(5):339-47. · 2.11 Impact Factor
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    ABSTRACT: The pharmacological properties of MA-2029, a novel motilin receptor antagonist, were investigated. In vitro, MA-2029 (1 to 30 nM) competitively inhibited motilin-induced contractions in isolated rabbit duodenal longitudinal muscle strips, with a pA2 value of 9.17+/-0.01 (n=5). However, contractile responses to acetylcholine and substance P were unaffected even at 1 microM of MA-2029. MA-2029 concentration-dependently inhibited the binding of [125 I]motilin to motilin receptors in a homogenate of rabbit colon smooth muscle tissue and membranes of HEK 293 cells expressing human motilin receptors. The pKi of MA-2029 was 8.58+/-0.04 in the rabbit colon homogenate (n=4) and 8.39 in the HEK 293 cells (mean of duplicate experiments). In vivo, orally-administered MA-2029 (3 to 30 mg/kg) dose-dependently inhibited colonic contractions induced by motilin (3 microg/kg, i.v.) in conscious rabbits. Inhibition was caused by all doses at 30 min after administration and by 10 mg/kg or more at 4 h after administration. The plasma concentration of MA-2029 correlated with its inhibitory effect. Furthermore, the oral administration of MA-2029 (0.3 to 3 mg/kg) also inhibited abdominal muscle contractions (an index of the visceral pain) induced by intravenous infusion of motilin (3 microg/kg/h) during colorectal distension in conscious rabbits. These results indicate that MA-2029 is an orally active, selective and competitive motilin receptor antagonist. It is suggested that this compound may be useful for gastrointestinal disorders associated with disturbed gastrointestinal motility such as irritable bowel syndrome.
    European Journal of Pharmacology 04/2008; 581(3):296-305. · 2.59 Impact Factor
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    ABSTRACT: 1. We examined effects of orally administered mitemcinal, an erythromycin-derived motilin agonist, on gastric emptying and antroduodenal motility in conscious normal dogs and conscious dogs with experimentally delayed gastric emptying. For comparison, we also examined the effects of orally administered cisapride. 2. Gastric emptying was assessed by adding paracetamol to the test meal and determining three of its pharmacokinetic parameters as indices of gastric emptying. Antroduodenal motility was assessed from the output of force transducers chronically implanted in the gastric antrum and duodenum. 3. In normal dogs, mitemcinal (0.25, 0.5 and 1 mg/kg) dose-dependently accelerated gastric emptying, significantly increasing all three indices at doses of 0.5 and 1 mg/kg; cisapride (1, 3 and 10 mg/kg) had no significant effect. Mitemcinal also dose-dependently stimulated antroduodenal motility in the interdigestive and digestive states. Cisapride, at 100-fold the dose, produced similar effects in the interdigestive state, but mixed results in the digestive state. 4. In dogs with delayed gastric emptying induced by subcutaneous clonidine (0.03 mg/kg), mitemcinal (0.25, 0.5 and 1 mg/kg) dose-dependently improved delayed gastric emptying, significantly increasing two of three indices at a dose of 1 mg/kg. Cisapride (1, 3 and 10 mg/kg) caused non-significant increases in the indices of gastric emptying, with roughly bell-shaped dose-response curves. The highest dose of mitemcinal (1 mg/kg) also stimulated antroduodenal motility. 5. In dogs with delayed gastric emptying induced by vagotomy, mitemcinal (0.125, 0.25 and 0.5 mg/kg) dose-dependently improved delayed gastric emptying, significantly increasing all three indices at doses of 0.25 and 0.5 mg/kg. Cisapride (3 mg/kg) restored the indices to roughly prevagotomy levels, but none of the increases was significant. Mitemcinal, at a dose of 0.25 mg/kg, also stimulated antroduodenal motility. 6. Because delayed gastric emptying is the basic characteristic of gastroparesis, the fact that mitemcinal accelerated gastric emptying in dogs with normal and delayed gastric emptying much more robustly than cisapride adds to the evidence that mitemcinal is likely to be useful for the treatment of patients with gastroparesis.
    Clinical and Experimental Pharmacology and Physiology 02/2008; 35(1):35-42. · 2.41 Impact Factor
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    ABSTRACT: Neither the presence of motilin receptors nor their action has been investigated in monkeys. The object of this study was to determine the effects of motilin and mitemcinal (GM-611), an erythromycin derivative, on the gastrointestinal tract in rhesus monkeys in vivo and in vitro. In in vivo investigations in conscious monkeys, both motilin and mitemcinal induced migrating motor complex-like contractions in the interdigestive state and also accelerated gastric emptying. In in vitro investigations, the presence of motilin receptors in the gastrointestinal tract was demonstrated by receptor binding assays. Motilin and mitemcinal contracted isolated duodenum strips in a concentration-dependent manner. In conclusion, rhesus monkeys may be useful for studying the physiological and pharmacological roles of the motilin agonistic mechanism because they show reactivity to motilin both in vivo and in vitro.
    Digestive Diseases and Sciences 12/2007; 52(11):3112-22. · 2.26 Impact Factor
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    ABSTRACT: The effects of mitemcinal (GM-611), an orally active motilin agonist, on defecation were investigated in rabbits and dogs. In normal rabbits, within 0-3 h of dosing, orally administered mitemcinal (2.5-10 mg kg(-1)) increased stool weight in a dose-dependent manner without causing loose stools. Sennoside (12-48 mg kg(-1)) also facilitated defecation within 2-9 h of oral administration, but the stools were significantly loosened. In the morphine-induced constipation model, the stool weight of morphine-treated rabbits (1 mg kg(-1)) was only 37.5% of that of untreated animals. Mitemcinal (0.5-20 mg kg(-1)) dose-dependently increased stool weight without increasing stool water content. At the highest dose of mitemcinal, stool weight recovered to 83.9% of that of untreated animals. In normal dogs, mitemcinal (0.3-3 mg kg(-1)) reduced the time to first bowel movement after oral administration without inducing diarrhoea at any dose. These results indicate that mitemcinal facilitates defecation without inducing severe diarrhoea. It is suggested that mitemcinal may be a novel therapeutic agent for constipation that enables easier control of the timing of defecation because of the early onset and short duration of its action, compared with sennoside.
    Neurogastroenterology and Motility 04/2007; 19(4):318-26. · 2.94 Impact Factor
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    ABSTRACT: The prokinetic effects of mitemcinal, an orally active motilin receptor agonist, on the lower gastrointestinal tracts were investigated in conscious dogs. Oral administration of mitemcinal (0.1-1 mg/kg) stimulated colonic motility, which was measured by chronically implanted force-transducers, as well as gastric motility in a dose-dependent manner. The gastrointestinal contractile activities induced by mitemcinal were inhibited by the continuous intravenous infusion of GM-109, a selective motilin receptor antagonist. Oral administration of mitemcinal (0.3-3 mg/kg) also accelerated bowel movement after feeding without inducing diarrhea in dogs. The results demonstrate that mitemcinal stimulates colonic motility via motilin receptors and the effect of mitemcinal on colonic motility may reflect bowel movement after feeding. Thus, mitemcinal could be a promising agent for treatment of not only the upper but also the lower gastrointestinal motility disorders.
    Inflammopharmacology 03/2007; 15(1):36-42.
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    ABSTRACT: 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 pA(2) 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 (125)I-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.
    Pharmacology 02/2007; 79(3):137-48. · 1.60 Impact Factor
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    ABSTRACT: The effects of mitemcinal (GM-611) on the gastrointestinal contractile activity were investigated using chronically implanted force transducers in conscious dogs and were compared with the effects of porcine motilin (pMTL), EM-523 and EM-574. In the interdigestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 induced the gastrointestinal contractile activity in a manner similar to pMTL. The contractile activity caused by mitemcinal was suppressed by continuous intravenous infusion of a motilin receptor antagonist. In the digestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 also stimulated the gastrointestinal contractile activity. Mitemcinal, EM-523 and EM-574 given intravenously increased the gastric contractile activity in a similar dose range; however, mitemcinal was approximately 10 times more potent than EM-523 and EM-574 when administered orally in the digestive state. These results indicate that the mitemcinal-induced gastrointestinal contractile activity operates via motilin receptors and possesses a higher activity than EM-523 and EM-574 when administered orally in conscious dogs in the digestive state. Mitemcinal may therefore be useful in the treatment of several gastrointestinal disorders involving dysmotility, such as gastroparesis and functional dyspepsia, even when administered orally.
    Pharmacology 01/2007; 79(4):223-35. · 1.60 Impact Factor
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    ABSTRACT: The effects of [Leu13]motilin were examined in vivo after its intravenous administration into anesthetized dogs and in vitro with isolated preparations of canine mesenteric artery. [Leu13]Motilin (0.1-10 nmol x kg(-1), i.v.) induced both strong and clustered phasic contractions in the gastric antrum and duodenum. At doses of over 1 nmol x kg(-1), [Leu13]motilin also produced transient decreases in arterial blood pressure, left ventricular pressure, maximum rate of rise of left ventricular pressure, and total peripheral resistance, and an increase in aortic blood flow and heart rate. A selective motilin antagonist, GM-109 (Phe-cyclo[Lys-Tyr(3-tBu)-betaAla] trifluoroacetate), completely abolished the gastric antrum and duodenal motor responses induced by [Leu13]motilin. In contrast, hypotension induced by [Leu13]motilin (1 nmol x kg(-1)) was unchanged in the presence of GM-109. In isolated mesenteric artery preparations precontracted with U-46619 (10(-7) M), [Leu13]motilin (10(-8)-10(-5) M) induced an endothelium-dependent relaxation, and this was inhibited by a pretreatment with N(omega)-nitro-L-arginine, a competitive inhibitor of NO synthase (10(-4) M). A high dose (10(-4) M) of GM-109 slightly decreased [Leu13]motilin-induced relaxation, and shifted the concentration-response curve of [Leu13]motilin to the right. However, the pA2 value (4.09) of GM-109 for [Leu13]motilin in the present study was conspicuously lower than that previously demonstrated in the rabbit duodenum (7.37). These results suggest that [Leu13]motilin induces hypotension via the endothelial NO-dependent relaxation mechanism and not through the receptor type that causes upper gastrointestinal contractions.
    Canadian Journal of Physiology and Pharmacology 01/1999; 76(12):1103-9. · 1.56 Impact Factor
  • Canadian Journal of Physiology and Pharmacology - CAN J PHYSIOL PHARMACOL. 01/1998; 76(12):1103-1109.
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    ABSTRACT: The pharmacological properties of the cyclic peptide Phe-cyclo[Lys-Tyr(3-tBu)-beta Ala-].trifluoroacetate (GM-109), a selective motilin antagonist, were investigated in the smooth muscle of the rabbit small intestine. GM-109 (0.1-3 microM) competitively inhibited contractions induced by porcine motilin (pMTL) in rabbit isolated duodenum longitudinal strips, with a pA2 value of 7.37 +/- 0.24. However, the contractile response to acetylcholine, to substance P, to prostaglandin F2 alpha and to KCl was unaffected by 10 microM GM-109 in the same preparation. Both GM-109 and pMTL competitively inhibited 125I-pMTL binding to motilin receptors in a homogenate of the rabbit small intestinal smooth muscle tissue. The pKi value of GM-109 and the pKd value of unlabeled pMTL were 7.99 +/- 0.04 and 9.25 +/- 0.06 (each n = 5), respectively. These results indicate that GM-109 is a selective and competitive motilin receptor antagonist in the smooth muscle of the rabbit small intestine. Thus this compound may be a useful pharmacological tool for examining the functional role(s) of motilin.
    Journal of Pharmacology and Experimental Therapeutics 06/1995; 273(2):624-8. · 3.89 Impact Factor
  • Gastroenterology 01/1995; 108(4). · 12.82 Impact Factor