Synthesis and Structure−Affinity Relationships of Novel <i>N</i>-(1-Ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with Potent Serotonin 5-HT₃ and Dopamine D₂ Receptor Antagonistic Activity

A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D2 and serotonin 5-HT3 receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT3 receptor along with moderate to high binding affinity for the dopamine D2 receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D2 receptor while keeping a potent serotonin 5-HT3 receptor binding affinity. As a result of structure−affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D2 and serotonin 5-HT3 receptors was much more potent than that of metoclopramide (dopamine D2 receptor; 23.3 nM vs 444 nM, serotonin 5-HT3 receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D2 and serotonin 5-HT3 receptors, while the corresponding (S)-53 had a potent serotonin 5-HT3 receptor binding affinity and a moderate dopamine D2 receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D2 and serotonin 5-HT3 receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D2 and serotonin 5-HT3 receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID50 values of 27.1 μg/kg, po and 136 μg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent

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 (∼50 mg/mL). Compound 6 exhibited excellent in vitro and in vivo antibacterial activity against some Gram-positive strains, including drug-resistant pathogens