Compound R_EC50 (nM)a

aData from ref. 56.

have been selected for safety assessment studies but results from ongoing analog syntheses suggested that greater intrinsic activity was possible.

The potency breakthrough was achieved by derivatizing 1'-(t-butoxycarbonyl)-spiro[lH-indene-1,4'-piperidine], which is an intermediate used in the synthesis of 20. Osmylation of the indene double bond afforded a diol that was elaborated to compound 28 whose intrinsic activity was slightly less than the corresponding spiroindane 20 as shown in Table 3 (56). However, hydroboration yielded a 1:1 mixture of alcohols that, after separation, afforded compounds 29 and 30. The latter with an EC50 = 0.6 nM in the rat pituitary cell assay is more than 10-fold as potent as compound 20 and the derived ketone analog 31 is nearly as potent. Unfortunately, when these analogs were tested orally in dogs they were only twice as active in elevating GH as compound 20 (56). Apparently they were not as bioavailable as the parent (20) possibly the result of carbonyl reduction and conjugation of the alcohol. To investigate the implications of this possibility, other polar substitu-ents with greater metabolic stability were introduced at the indane benzylic position.

Table 4

Spiroindanylpiperidine Optimization q/x"^

Compound_R_EC5q (nM)a

0 0

Post a comment