Hiroshi Koga

Design of potent K+ channel openers by pharmacophore model

Abstract A pharmacophore model which explains rationally structure-activity relationships of chemically diverse potent K + channel openers, has been constructed. Potent benzopyran derivatives with thioamide, amide, and ( N -cyano)amidine groupa at the 4-position have been designed using the model.

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

Abstract Based on the acid decomposition mechanism of erythromycin A, 11-deoxy-12-O-methyl-11-oxo-8,9-anhydroerythromycin A 6,9-hemiacetals were designed and synthesized. GM-611 (11) and the derivatives 8 and 8 were acid-stable and showed potent in vitro and in vivo motilin agonistic activities, and these compounds were thought to be promising orally active prokinetic agents.

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

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.

Effects of Mitemcinal (GM-611), an Acid-Resistant Nonpeptide Motilin Receptor Agonist, on the Gastrointestinal Contractile Activity in Conscious Dogs

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.

The Activity of AA-193, A New Uricosuric Agent, in Animals

A new uricosuric agent, 5-chloro-7, 8-dihydro-3-phenylfuro[2, 3-g]-1, 2-benzisoxazole-7-carboxylic acid (AA–193), was compared with other uricosurics in the rat, mouse and cebus monkey.

ORAL MITEMCINAL (GM-611), AN ERYTHROMYCIN-DERIVED PROKINETIC, ACCELERATES NORMAL AND EXPERIMENTALLY DELAYED GASTRIC EMPTYING IN CONSCIOUS DOGS

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.

N,N-disubstituted benzopyran-4-(N′-cyano)carboxamidines, cromakalim analogs with selective activity for guinea pig trachealis

N-Cyano-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamidines have been synthesized. Some of these compounds exhibited selective activity for guinea pig trachealis.

6-Substituted 2,2-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openers.

In the course of our study to find an ideal antihypertensive potassium channel opener (KCO), N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-ben zopyran-4-carboxamide (13f, KC-515) showed a highly potent, slow and long-lasting antihypertensive effect with reduced reflex tachycardia, together with the beneficial effects of KCO such as improvement in lipid metabolism. These profiles identify KC-515 as a potential candidate. In conscious spontaneously hypertensive rats (SHR), the onset of the hypotensive effect of KC-515 (13f) was gradual and the maximum response was attained at around 6 h after dosing. The duration of action was over 18 h for 0.1 mg/kg. When administered to Zucker rats for 2 weeks with 0.03-0.3 mg/kg po range in the antihypertensive doses in hypertensive rat models, KC-515 (13f) significantly and dose-dependently reduced serum triglycerides to less than 70% of control without affecting total cholesterol.

Mitemcinal (GM-611), an orally active motilin agonist, facilitates defecation in rabbits and dogs without causing loose stools

Abstractu2002 The effects of mitemcinal (GM‐611), an orally active motilin agonist, on defecation were investigated in rabbits and dogs. In normal rabbits, within 0–3u2003h of dosing, orally administered mitemcinal (2.5–10u2003mgu2003kg−1) increased stool weight in a dose‐dependent manner without causing loose stools. Sennoside (12–48u2003mgu2003kg−1) also facilitated defecation within 2–9u2003h of oral administration, but the stools were significantly loosened. In the morphine‐induced constipation model, the stool weight of morphine‐treated rabbits (1u2003mgu2003kg−1) was only 37.5% of that of untreated animals. Mitemcinal (0.5–20u2003mgu2003kg−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 (0.3–3u2003mgu2003kg−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.

Mitemcinal (GM-611), an orally active motilin receptor agonist, accelerates colonic motility and bowel movement in conscious dogs.

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 (0.1–1xa0mg/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 (0.3–3xa0mg/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.