Molidustat Sodium

Hypoxia-inducible factor 2-alpha (HIF-2α), a critical transcription factor, forms a heterodimer with aryl hydrocarbon receptor nuclear translocator (ARNT) to drive the transcription of erythropoietin (EPO), a key regulator of erythropoiesis. Activation of this pathway plays a pivotal role in the treatment of anemia. By discovered structure-based virtual screening and pharmacological assays, we herein discovered an amide thiazole AT-1 that bound to HIF-2α with a K_D of 2.63 μM, and enhanced the stability of the HIF-2α-ARNT heterodimer. Molecular docking and site-directed mutagenesis analysis revealed the critical roles of His293 and Tyr307 in the binding of AT-1 to HIF-2α. Pharmacological studies showed that AT-1 (10, 20, 40 μM) dose-dependently enhanced both the transcription and secretion of EPO in 786-O and Hep3B cells. In zebrafish (Danio rerio), AT-1 (10 or 50 μM) exhibited favorable safety profiles and, when combined with the prolyl hydroxylase (PHD) inhibitor Molidustat (10 μM), effectively mitigated doxorubicin-induced anemia. In adenine-induced chronic kidney disease (CKD) mouse model, combined administration of AT-1 (50 mg·kg^-1·d^-1, i.p.) and Molidustat (10 mg·kg^-1·d^-1, i.p.) for 15 days produced stronger effects on increasing EPO levels and alleviating anemia than Molidustat alone, further supporting the therapeutic potential of AT-1 in CKD-related anemia.

Erythropoietic effects of molidustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, occur in anemic cats with chronic kidney disease (CKD).

To evaluate the effectiveness and safety of molidustat in managing anemia in cats with CKD.

Seventy-five client-owned anemic cats with CKD in the effectiveness and safety phase and 64 in the safety continuation phase.

Multicenter, randomized, double-masked, placebo-controlled field study. Cats in the 28-day effectiveness and safety phase received 5 mg/kg of molidustat (n = 40) or a control product (CP; n = 35), once daily for 28 days. During the 20-week safety continuation phase, all cats received 5 mg/kg molidustat in 28-day treatment cycles once PCV declined to < 28%. Individual cat treatment success, defined as a ≥ 4% point increase in hematocrit (HCT) compared to baseline, was evaluated on day 28. Safety was assessed throughout both phases.

Proportion of molidustat-treated cats with treatment success on day 28 (68% ± 7.4%; 95% CI, 51.45-80.28) was significantly higher compared to CP cats (17% ± 6.4%; 95% CI, 7.80-33.59; P < .001). During the safety continuation phase, median treatment cycle duration was 28 days with treatment intermission medians ranging from 11 to 18 days. There was no evidence of adverse effects attributed to molidustat when administered alone or in combination with other medications.

Molidustat significantly increased HCT values in treated cats compared to CP cats. Repeated 28-day treatment cycles were well-tolerated. Molidustat is an effective and safe treatment for long-term management of anemia in cats with CKD.