A first in man study to evaluate the safety, pharmacokinetics and pharmacodynamics of RP7214, a dihydroorotate dehydrogenase inhibitor in healthy subjects

Abstract

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that is essential for pyrimidine de novo synthesis. Rapidly growing cancer cells and replicating viruses are dependent on host cell nucleotides, the precursors of which are provided by DHODH. Hence, DHODH becomes an ideal target for pharmacological intervention. RP7214 is a potent and selective inhibitor of human DHODH and has shown antiviral and antileukaemic activity in preclinical studies. This paper describes the phase I study that evaluated the safety and pharmacokinetics of single and multiple ascending doses (SAD and MAD) and the food effect of RP7214 in healthy volunteers (HVs). The study was a randomized, double‐blind, placebo‐controlled trial of single dose (100, 200 and 400 mg QD), multiple doses (200 and 400 mg BID for 7 days) and a food effect study at a single dose of 200 mg. A total of 18, 12 and 12 HVs were enrolled in the SAD, MAD and food effect parts of the study, respectively. RP7214 was well tolerated at all dose levels. There were 20 treatment‐emergent adverse events (TEAEs) reported, out of which most were mild to moderate in severity while three TEAEs were grade ≥3. RP7214 showed accumulation on multiple dosing. Steady‐state concentrations were reached within about 3‐6 days. The mean plasma half‐life at steady‐state was 12.8 hours (9.9‐15.3). Food did not impact the absorption of RP7214. Inhibition of DHODH, as evidenced by increased dihydroorotate levels, was observed, confirming target engagement. The high systemic exposure with a favourable safety profile shows potential for the development of RP7214 in SARS‐CoV‐2 and acute myeloid leukaemia (NCT04680429).

Development of a Potent Nurr1 Agonist Tool for In Vivo Applications

“…1 activated human Nurr1 also in its native full-length form as a monomer (NBRE, EC 50 = 0.3 ± 0.1 μM Figure 1 e) and RXR/Nurr1 heterodimer (DR5, EC 50 = 0.4 ± 0.2 μM, Figure 1 e) and bound to the recombinant Nurr1 LBD with submicromolar affinity ( K d = 0.7 μM) in isothermal titration calorimetry (ITC, Figure 1 f). To further validate the effects of 1 as directly Nurr1-mediated and exclude artifacts of DHODH inhibition, we studied the effects of the structurally related DHODH inhibitors 25 2 , farudodstat, 26 MEDS433, 27 RP7214, 28 and AG-636 29 ( Figures 1 g and S2 ). 1 and its deuterated analogue 2 activated Nurr1 in the Gal4 hybrid assay and on the native NBRE.…”

Discovery a series of novel inhibitors of human dihydroorotate dehydrogenase: Biological activity evaluation and molecular docking

“…When administered orally in combination with cisplatin or cyclosporine A, it can easily cause thrombocytopenia and mucosal inflammation, and the treatment window is narrow, limiting its clinical application (Horvat & Lesinski, 2022; Khairy et al., 2022; Peters, 2018; Zi et al., 2023); leflunomide is the only h DHODH inhibitor that has been marketed for the treatment of rheumatoid arthritis, but long‐term use can cause adverse reactions such as liver enzyme abnormalities, hypertension, diarrhea, and rash (Hong et al., 2023; Kilic et al., 2023; Lycke et al., 2023; Paik, 2021; Wu et al., 2023). Therefore, searching for efficient, low toxicity, and novel structure h DHODH inhibitors remains a research hotspot in the treatment of autoimmune diseases (Nair et al., 2023; Petrović et al., 2023; Rawdha et al., 2023).…”