CS-2374

TC-G-1008 shows selectivity over a panel of kinases (IC ₅₀ s>10 μM) and does not exhibit relevant binding affinity for the related ghrelin and neurotensin-1 receptors (IC ₅₀ s>30 μM). In HEK293-GPR39 cells, GPR39-C3, which is a positive allosteric modulator, activates cAMP production (downstream of Gs), IP1 accumulation (downstream of Gq), SRF-RE-dependent transcription (downstream of G12/13), and β-arrestin recruitment. GPR39-C3 induces dose- and time-dependent loss of response in cAMP production by second challenge of the compound.

Rat and mouse plasma protein binding for TC-G-1008 is measured as 99.3% and 99.1%, respectively. TC-G-1008 is orally bioavailable in mice and robustly induces acute GLP-1 levels. Upon single oral doses of 10, 30, and 100 mg/kg of aqueous suspensions in 0.5% methylcellulose/0.1% Tween 80, TC-G-1008 achieves, between 1 and 1.5 h, maximal exposures of 1.4, 6.1, and 25.3 μM, respectively.