GLPG3312 is a selective and potent pan-SIK inhibitor with the advantage of oral activity, with IC50=0.6-2.0 nM for SIK1, SIK2 and SIK3, and exhibits anti-inflammatory and immunomodulatory activity in both human primary myeloid cells and mouse models.

Monocyte-derived macrophages (MdMs): 34 nM, Primary CD14⁺ monocytes(human): 17 nM

In LPS (100 ng/mL)-stimulated human primary CD14⁺ monocytes and monocyte-derived macrophages (MdMs),GLPG3312 inhibited TNFα release in monocytes(IC₅₀ 17 nM) and in MdMs(IC₅₀ 34 nM). At a concentration of 20 μM, GLPG3312 enhanced IL-10 secretion by 14.8-fold in monocytes and 2.8-fold in MdMs. Cells were preincubated with the compound for 1 hour before LPS stimulation, and cytokine levels were measured at 4 hours for monocytes and at 2 and 20 hours for IL-10 and TNFα, respectively, in MdMs[1].

In Balb/c mice, GLPG3312 was administered p.o. at 0.3, 1, or 3 mg/kg, followed by i.p. LPS (100 μg) 15 min later. Plasma cytokines measured at 1.5 h post-LPS showed TNFα inhibition of 27.0%, 57.2%, and 77.5%, respectively, and IL-10 increases of 1.3-, 2.4-, and 3.1-fold at the same doses. GLPG3312 also exhibited favorable PK, with oral bioavailability of 60% in mice, 41.4% in rats (5 mg/kg), and 45.5% in dogs (30 mg/kg), along with low CL and acceptable t₁/₂[1].