Seven healthy volunteers and 3 hospitalized patients were given the same diet for 6 days. The mean intake of cholesterol was 359 mg/day. There was a large difference in the fecal amount of cholesterol and coprostanol amongthe subjects. The ratio of coprostanol/cholesterol ranged from 0.01 to 4.27. The subjects whose feces contained smaller amountof coprostanol excreted larger amounts of jS-sitosterol and crude fiber, suggesting that the various activities of intestinal flora were lower than the other subjects. The difference in the activity of intestinal flora to convert cholesterol into coprostanol was ascertained by incubating the feces anaerobically with egg yolk in vitro. It was also demonstrated that cholesterol was synthesized de novo and the amount corresponded to 0.1-0.6 g/day. The amounts of sterols in the feces of the other 17 hospitalized patients were also determined and there was an inverse relationship between the serum cholesterol and coprostanol/cholesterol ratio in the feces. These results suggested that the conversion of cholesterol into coprostanol by the intestinal flora might have an important role in the regulation of serum cholesterol level.
In the joint experimental and computational efforts reported here to obtain novel chemical entities as growth hormone secretagogues (GHSs), a small database of peptides and non-peptides known to have GHS activity was used to generate and assess a 3D pharmacophore for this activity. This pharmacophore was obtained using a systematic and efficient procedure, "DistComp", developed in our laboratory. The 3D pharmacophore identified was then used to search 3D databases to explore chemical structures that could be novel GHSs. A number of these were chosen for synthesis and assessment of their ability to release growth hormone (GH) from rat pituitary cells. Among the compounds tested, those with a benzothiazepin scaffold were discovered with micromolar activity. To facilitate lead optimization, a second program, a site-dependent fragment QSAR procedure was developed. This program calculates a library of chemical and physical properties of "fragments" or chemical components in a known pharmacophore and determines which, if any, of these properties are important for the observed activity. The combined use of the 3D pharmacophore and the results of the site-dependent fragment QSAR analysis led to the discovery and synthesis of a novel series of potent GHSs, a number of which had nanomolar in vitro activity.
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