Atsushi Tsubaki

Studies on the Synthesis of Cholecystokinin A Receptor Antagonists. II. Synthesis and Cholecystokinin A Receptor Inhibitory Activities of Sulfur-Containing Amide-Carboxylic Acid Derivatives

A number of sulfur-containing amide-carboxylic acid derivatives were synthesized and tested for cholecystokinin A (CCK-A) receptor inhibitory activity in order to study structure-activity relationships. Significant CCK-A receptor inhibitory activities were found in only two series, that is, sulfoxide-carboxylic acid derivatives (9) and sulfone-carboxylic acid derivatives (10). As the most preferred compound, 5-(3,4-dichlorophenylsulfonyl)-4-(N,N-dipentylcarbamoyl)pent anoic acid (10n) was selected.

新規CCK-A受容体拮抗薬KSG-504の行動薬理学的研究

The effects of KSG-504 after intravenous administration on behavior and other central functions were studied. KSG-504 did not affect the general behavior of dogs up to the dose of 30 mg/kg, but the drug (100 mg/kg, i.v.) caused vomiting in 3 out of the 5 dogs. Moreover, KSG-504 (1-30 mg/kg, i.v.) had no effects on spontaneous motility, thiopental-induced sleep, acetic acid-induced writhing in mice and satiety in rats. A high dose of CCK-8 (100 micrograms/kg or more) suppressed spontaneous motility, writhing and satiety, and prolonged sleep when administered subcutaneously. The behavioral changes induced by CCK-8 were antagonized by KSG-504 in a dose-dependent manner (1-30 mg/kg, i.v.). When KSG-504 was administered intravenously to rabbits at the dose of 10 mg/kg or 0.5 mg/kg/min for 120 min, we could not detect the drug in the cerebrospinal fluid, indicating that KSG-504 does not cross the blood-brain barrier after peripheral administration of the drug. Thus, the inhibitory effect of KSG-504 on CCK-8-induced behavioral changes may be the result of antagonism at peripheral CCK-A receptors.

A practical synthesis of an orally potent renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-{N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naphthyl)propionyl]-L-histidyl}aminobutyrate

The practical synthesis of an orally potent human renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-{N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naphthyl)propionyl]-L-histidyl}-aminobutyrate, is presented. Optically pure cyclohexylnorstatine isopropyl ester (P1–P1′ moiety) was diastereoselectively and simply prepared from L-phenylalanine methyl ester. In a one-pot reaction, N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naphthyl)propionyl]-L-histidine methyl ester (P4–P2moiety) was conveniently hydrolysed, protected with a Boc group attached to the side-chain imidazole function, and coupled with the cyclohexylnorstatine ester to give the optically pure target renin inhibitor.