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Compound_R_EC5q (nM)a

"Data from ref. 56. bUnpublished results.

Our initial approach involved introducing and derivatizing an aza group at the indane benzylic position. As summarized in Table 4, the unsubstituted spiroindoline derivative 32 raised rat pituitary cell potency slightly. However, the N-acetyl and N-methanesulfonyl derivatives 33 and 34 were markedly more potent (57). Other acyl and sulfonyl analogs are active at this position but attention focused on compound 34 (EC50 = 1.8 nM) with the expectation that metabolic stability and minimal size would favor good oral activity. Nevertheless, despite excellent intrinsic activity, only one of two dogs at both the 0.5 mg/kg and 1.0 mg/kg oral dose levels responded to 34 with good GH elevations (58).

Concurrently, the D-tryptophan component of compound 20 was being replaced with other D-amino acids some of which are shown in Table 5. Napthalene in compounds 39 and 40 was a surprisingly poor replacement for the indole group of compound 20 especially since it is used in GHRP-1 and GHRP-2 as an indole surrogate and in a series of highly active small peptide derivatives described by McDowell et al. (25).

However, the phenylpropyl and benzyloxymethyl compounds 37 and 38, respectively, retained intrinsic potency quite comparable to that of 20 and even the activity of the phenethyl

Table 5

Aromatic Amino Acid Variations c=o O

Compound R EC50 (nM)a

Compound R EC50 (nM)a

aData from ref. 57.

analog 36 was only twofold weaker than 20. The oral potency of 36 in dogs was comparable to 20 but compounds 37 and 38 showed good elevations of growth hormone in oral doses as low as 0.5 mg/kg and thus were approximately fourfold more active orally than compound20 (57).

These and other indole replacements were tried in the spiroindoline series some of which are shown in Table 6. Activities paralleled those of the corresponding spiroindane derivatives and peaked in the phenylpropyl and benzyloxymethyl analogs 43 and 44, respectively. P-Napthalene in compound 41 was a poor replacement for indole. The substitution of sulfur for oxygen in compound 45 resulted in a 10-fold loss in cell culture potency apparently indicating a limitation in the optimum length of the amino acid side-chain. The latter need not contain an aromatic residue as indicated by comparable activities of compounds 42 and 46. It was also reported by Patchett et al. (54) that the (l)- isomer of compound 38 was only poorly active (EC50 = 500 nM), which led to the suggestion that this amino acid position might correspond to the 2-D-Trp position of GHRP-6.

Table 6

Discovery of L-163,191 (MK-0677)-Compound 44

Table 6

Discovery of L-163,191 (MK-0677)-Compound 44

Data from ref. 54. Unpublished results cData from ref. 37.

Data from ref. 54. Unpublished results cData from ref. 37.

The compounds shown in Table 6 were screened in dogs for growth hormone elevation following oral administration. Efficacies were best with compound 43 and compound 44 (L-163,191) and, of these two, the latter seemed to be consistently more potent.

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