Structure Activity Studies Leading to MK0677

The bioavailability problem had not been solved with 19 since it failed to elevate GH in beagles after oral administration at 5 mg/kg. To address this deficit, attention was

Table 2

Spiroindanylpiperidine Lead-Modification of the Amino Acid Side-Chain

Table 2

Spiroindanylpiperidine Lead-Modification of the Amino Acid Side-Chain

Data from ref. 55.

focused on the amine side chain in the belief that urea functionality and the strongly basic quinuclidene group might be responsible for poor uptake from the GI tract. Preference for D-tryptophan stereochemistry was established and then we turned to the amino side-chains that were particularly useful with the benzolactams, this time with success, as illustrated in Table 2. Compound 25 containing the potency enhancing 2-hydroxypropyl group of the benzolactam L-692,585 (4) had the highest intrinsic potency (EC50 = 2.6 nM) among these analogs of19. Nonetheless, the most orally active of these early analogs was compound 20. It produced good GH elevation following an oral dose of 2 mg/kg in dogs despite an EC50 of only 14 nM in the rat pituitary cell assay (55).

The further characterization of 20 included IC50s >10 ^M in twenty-four G-protein linked receptor assays. This specificity was very welcome so early in the project given our categorization of the lead as a privileged structure derivative. Also its bioavailability in rats after iv and po administration was determined to be >40% (55). The lead might

Table 3

Spiroindanylpiperidine Modifications

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