RESUMEN
BACKGROUND: 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which is an enzyme that converts cortisone to cortisol, plays a role in the regulation of glucose metabolism and inflammation. J2H-1702 is a novel 11ß-HSD1 inhibitor, and the inhibition of 11ß-HSD1 has been shown to improve insulin sensitivity, reduce inflammation, and prevent the development of nonalcoholic steatohepatitis (NASH) in preclinical models. AIMS: We aimed to assess the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability of J2H-1702 after a single-dose oral administration. METHODS: A randomised, double-blinded, placebo-controlled, single-dose, dose-escalation study was conducted on 50 healthy volunteers. Blood and urine samples were collected to assess the PK and PD of J2H-1702. RESULTS: The peak plasma concentration of J2H-1702 was observed at 2-2.9 h after a single-dose oral administration. J2H-1702 reduced 11ß-HSD1 activity compared to the placebo at all dose levels. The drug reached its maximal inhibitory effect within 12-24 h post-dose administration, and the inhibitory effect was maintained till 1 day after administration of the study drug. The drug showed typical first-order elimination kinetics, with a mean elimination half-life of 9.8-14.7 h. Systemic exposure to J2H-1702 increased in a dose-dependent manner. J2H-1702 was well tolerated after a single oral administration of up to 300 mg. A total of 11 treatment-emergent adverse events (TEAEs) occurred in seven (14%) participants, all of which were mild and resolved spontaneously. The most common TEAE was diarrhoea (8%), followed by dizziness (4%). CONCLUSIONS: The results of this study suggest that J2H-1702 could be developed as an effective therapeutic option for NASH.