C-Terminal Modifications Boost Potency of Growth Hormone Secretagogue NN703

Growth hormone secretagogues (GHS) are compounds that stimulate the body's natural production and release of growth hormone (GH), which plays a crucial role in metabolism, muscle growth, and bone density. Existing orally active GHS like NN703 show promise for treating conditions such as growth hormone deficiency or age-related muscle wasting (sarcopenia). However, optimizing their potency and pharmacokinetic properties remains a key challenge. This study specifically aimed to develop more potent analogues of NN703 by modifying its C-terminal structure.

The study identified several C-terminal modified analogues with significantly enhanced GHS activity compared to the parent compound. The most potent analogue, NN703-S12, demonstrated an EC50 of 0.75 nM for stimulating GH release, representing a remarkable 2.6-fold increase in potency over the original NN703's EC50 of 1.95 nM. Overall, 15 of the 28 synthesized compounds showed activity comparable to or exceeding NN703, with 5 compounds exhibiting potency greater than 2-fold. Growth hormone secretion was consistently increased by up to 4.8-fold at 100 nM concentrations for the lead compounds, a statistically significant improvement over vehicle control (p<0.001). These findings confirm that specific C-terminal modifications can dramatically improve the intrinsic activity of NN703.