Development of a long-acting unbiased GIP receptor agonist for studies of GIP's role in bone metabolism.

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates bone remodeling postprandially. Species variations complicate the development of long-acting agonists with similar effects on rodent and human GIP receptors (GIPR). We created a series of long-acting molecules suitable for rat studies based on human GIP, stabilized with Aib insertion in position 2, lipidations in the middle region (compounds 1-4: positions 14/16/17/20) or the C-terminus (compound 5: position 40), and elongation with an exendin-4 tail in the C-terminus (Cex). The compounds were tested in vitro on the human and rat GIPR for cAMP accumulation, beta-arrestin recruitment and internalization. Pharmacokinetic profiling in rats was completed for two compounds, and one was selected for bone remodeling studies in rats (measurements of C-terminal telopeptide (CTX) and procollagen type 1 N-propeptide). All five compounds retained the potency and efficacy of native (human and rat) GIP in cAMP accumulation and arrestin recruitment on human and rat GIPR with no differences in relative activities from native GIP. Only compound 3 induced internalization like species-matched GIP on respective receptors and was chosen for in vivo assessments in rats. Mean T1/2 was 9.1 h, and it decreased plasma levels of CTX compared to vehicle treatment following 1000 µg·kg-1 injections. In conclusion, the long-acting, unbiased compound 3 (hGIP(1-30-Cex)/Aib2/C16-diacid moiety in position 17), with retained activity for the human and rat GIPR, is suitable for bone remodeling studies in rats; hence, a useful tool compound for future research of GIP's therapeutic potential in bone-related diseases.