Synthesis of phenoxyacetic acid derivatives as highly potent antagonists of gastrin/cholecystokinin-B receptors. III

In order to improve the biological characteristics of DA-3934 (5), a novel gastrin/cholecystokinin (CCK)-B receptor antagonist, phenoxyacetic acid derivatives replacing the N-methyl-N-phenylcarbamoylmethyl moiety of 5 with various alkyl chains have been synthesized and their biological activity evaluated. The relationship between the structure of these compounds and their human gastrin receptor binding affinity showed that there should be the optimal size among the various N-alkyl chains. Also a significant increase in the receptor binding affinity was achieved by several compounds. Among those compounds, 2-[3-[3-[N-cyclohexylmethyl-N-[2-(N-methyl-N- phenylcarbamoylmethoxy)phenyl]carbamoylmethyl]ureido]phenyl]acetic acid (22c) and (±)-2-[3-[3[N-[2-(N-methyl-N-phenylcarbamoylmethoxy)phenyl]-N-(3- methylpentyl)carbamoylmethyl]ureido]phenyl]acetic acid (22h) exhibited high affinity for human gastrin receptors and were also more potent inhibitors in a pentagastrin-induced gastric acid secretion model than the parent compound, 5. The ED(50) values of these compounds when administered intraduodenally to rats were 0.12 and 0.63 mg/kg, respectively.