Skeletal structures very similar to those of four known inhibitors were automatically output from our computer program LEGEND, based on the three-dimensional structure of the active site of the target enzyme, dihydrofolate reductase. Besides them, the program output novel promising structures that are stable intra- and intermolecularly. This result strongly supports the usefulness of this method for rational lead generation. New lead compounds can be obtained, not relying on chance or trial and error, if appropriate structural selection and modification of the output structures are made.
In connection with the known antisecretory activity of the benzotriazepinone (1) and the pyridylurea (2), novel pyridotriazepinones (3 and 4) have been synthesized. They were prepared from aminopyridinecarboxylic acids via several steps, and their structures were confirmed by X-ray crystallographic analysis. Attempts to synthesize the positional isomer (24) resulted in formation of the pyridotriazine (25 or 26). Some of these compounds showed moderate antisecretory activity in rats.
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