Conclusions

The GHRPs were discovered by Cyril Y. Bowers and his colleagues in the late 1970s. Through Dr. Bowers' dedicated efforts, their potency and in vivo properties were perfected culminating in clinical demonstrations of sustained growth hormone release. Efficacy as measured by growth improvements in GH-deficient children has been demonstrated and other possible uses are being studied. It is remarkable that these secreta-

gogues were developed without knowledge of the yet unidentified natural hormone which they presumably mimic.

In its discovery phases, the research that ultimately produced MK-0677 drew heavily upon the structure activity studies that led to GHRP-6, GHRP-2, GHRP-1, and especially benzolactam L-692,429. The work at Merck illustrates the value of privileged structure derivatization and directed screening in the design of peptidomimetics. Nonpeptide selections for screening and for exploratory synthesis reflected the essential structural features of the GHRPs and, remarkably, agonist activity was found in leads whose sizes are considerably less than the GHRPs. At the time only small molecule agonists were known of the opiate peptides.

Even with small molecule peptidomimetic leads, potency, selectivity, and good oral bioavailability were only achieved through the efforts of many chemists, biologists, and drug metabolism specialists. Clinical studies have been undertaken to determine if MK-0677 and other GH secretagogues will make a contribution to medicine. Regardless of that outcome, the potency and selectivity of [35S]-MK-0677 played an important role in the identification and cloning of the GHS receptor. The awaited next step in the GHRP story is the identification of the putative natural hormone. When that is achieved, our knowledge of the regulatory controls of pituitary growth hormone secretion will have reached an additional level of understanding.

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