Yoshimi Hirokawa

Novel and potent human and rat β3-Adrenergic receptor agonists containing substituted 3-indolylalkylamines

A novel series of 2-(3-indolyl)alkylamino-1-(3-chlorophenyl)ethanols was prepared and evaluated for in vitro ability to stimulate cAMP production in Chinese hamster ovary cells expressing cloned human beta(3)-AR. The optically active 30a was found to be the most potent and selective human beta(3)-AR agonist in this series with an EC(50) value of 0.062nM. In addition, 30a selectivity for human beta(3)-AR was 210-fold and 103-fold that for human beta(2)-AR and beta(1)-AR, respectively. Furthermore, 30a showed potent agonistic activity at rat beta(3)-AR.

Water-soluble pleuromutilin derivative with excellent in vitro and in vivo antibacterial activity against gram-positive pathogens.

Although earlier pleuromutilin analogues showed potent in vitro antibacterial activity against some Gram-positive pathogens, their in vivo efficacy was low because of insufficient pharmacokinetic properties. We designed novel thioether pleuromutilin derivatives having a purine ring as a polar and water solubilizing group and identified a promising pleuromutilin analogue 6 with good solubility in water ( approximately 50 mg/mL). Compound 6 exhibited excellent in vitro and in vivo antibacterial activity against some Gram-positive strains, including drug-resistant pathogens.

A novel series of 6-methoxy-1H-benzotriazole-5-carboxamide derivatives with dual antiemetic and gastroprokinetic activities

A novel series of 6-methoxy-1H-benzotriazole-5-carboxamide derivatives with a medium perhydroazacycle ring in the amine moiety were prepared, and their antiemetic and gastroprokinetic activities were evaluated. Among them, N-(1-ethylhexahydroazepin-3-yl)-, N-(1-ethyloctahydroazocin-3-yl)- and N-(1-ethyloctahydroazonin-3-yl)-6-methoxy-1H-benzotriazole-5-carbo xamides (24, 36, 37) showed a potent antiemetic activity (inhibition of apomorphine-induced emesis in dogs) along with gastroprokinetic activity (gastric emptying in rats).

Synthesis and resolution of (±)-N-[1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide by preferential crystallization

Abstract (±)- N -[1-Methyl-4-(3-methylbenzyl)hexahydro-1 H -1,4-diazepin-6-yl]-1 H -indazole-3-carboxamide (±)- 1 was prepared from N -methyl- N ′-(3-methylbenzyl)-ethylenediamine 5 and 2-(1-benzyloxycarbonyl-1 H -indazole-3-carbonylamino)propenal 4 and was found to exist as a racemic mixture based on the melting point, solubility, infrared spectrum, and X-ray diffraction pattern. Resolution by a preferential crystallization of (±)- 1 and successive recrystallization from acetone gave the enantiomerically pure ( R )-isomer, which showed a potent and selective 5-HT 3 receptor antagonistic activity.

Synthesis of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)nicotinamides and their affinities for 5-HT3 and dopamine D2 receptors

A series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)nicotinamide derivatives were prepared and evaluated for their binding to 5-HT3 and dopamine D2 receptors. Among them, the 5-bromo-2-methoxy-6-methylaminonicotinamide 16 and its (R)-isomer were found to have potent affinities for both receptors. The affinities of (R)-16 for 5-HT3 and dopamine D2 receptors are approximately 3-fold higher than those of the corresponding benzamide (R)-1 (IC50: 1.1 and 12 nM vs. 2.9 and 35 nM, respectively).

A novel series of N-(hexahydr-1,4-diazepin-6-yl) and N-(hexahydroazepin-3-yl)benzamides with high affinity for 5-HT3 and dopamine D2 receptors

A novel series of benzamides with a hexahydro-1,4-diazepine or hexahydroazepine ring in the amine moiety were prepared, and their binding affinities for 5-HT3 and dopamine D2 receptors were evaluated. The R isomer of the 1-ethyl-4-methylhexahydro-1,4-diazepinylbenzamide (R)-22 had potent affinity for both receptors. The R-enantiomer of the corresponding 1-ethylhexahydroazepinylbenzamide 28 showed potent affinity for dopamine D2 receptors with reduced affinity for 5-HT3 receptors, while the S isomer was found to be a potent and selective 5-HT3 receptor antagonist.