The Privileged Structure Approach

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The Spiroindanylpiperidine Lead From Screening

The discovery of the benzolactams demonstrated that potent nonpeptide GH secreta-gogue agonists could be discovered in the 500-600 Kda molecular weight range. This was quite a breakthrough. Although there were many nonpeptide antagonists known at the time, the only precedent for non-peptide agonists were the opioid peptide mimetics including morphine and the analgesic benzodiazepine tifluadom. Compound screening continued after the benzolactam discovery in an effort to find different core structures that might more easily be converted to an orally active drug. There was precedent for additional leads in numerous structural variants of morphine especially since GHRP-6 was itself derived from enkephalin.

Indeed another lead, compound 10, was found by directed screening. This camphor-sulfonamide originated in a program from which eventually came orally active oxytocin antagonists such as compound H (43) (Fig. 5).

In an effort to enhance the potency and specificity of this new lead (EC50 = 0.30 ^M (GH secretagogue); IC50 = 0.068 ^M (oxytocin antagonist), analogs containing a tolyl-piperazine or a spiroindanylpiperidine were synthesized. Both series were comparably active and some of the latter type are shown in Table 1 (44).

Like the lead compound 10, the most active of its analogs contains a nipecotic acid part-structure. This was a surprise to us since we hoped the amino acid side-chains that conferred high potency to the benzolactams might do likewise in the camphorsulfonamide series. Even an N-2-hydroxypropyl substituent (17) that was taken from the highly active benzolactam 4 (L-692,585) did not afford sufficient potency to justify in vivo testing.

Nevertheless, the discovery of this camphorsulfonamide series was important. It demonstrated that GH secretagogue agonist activity need not be limited to a narrowly defined pharmacophore and it contributed to the selection of the spiroindanylpiperidine nucleus for use in a "privileged structure" derivatization project. The term "privileged structures" was introduced by Evans et al. (45) to describe core structures that recur frequently in receptor ligands and whose derivatization, they suggested, was a useful way of discovering agonist and antagonist leads. Their design of cholecystokinin (CCK)-A antagonists was based on the "privileged" benzodiazepine core of the natural product CCK-A antago-

Table 1

Camphorsulfonamide Structure—Activity Relationships


ECso (nM)a


ECso (nM)a

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