CVN45502 (CVN 45502) is a potent, orally bioavailable, highly selective orexin 1 receptor (Hcrtr1, OX1R) antagonist with binding affinity (pKi) of 7.86 (human Hcrtr1), significantly reduces feeding and body weight in diet-induced obese (DIO).
CVN45502 displays 1000-fold selectivity over human Hcrtr2 receptor (pKi=4.66), CVN45502 (10 µM) also does not engage a broad panel of 125 receptors, ion channels, enzymes and transporters.
CVN45502 is highly brain penetrant with a concentration in the brain of 1.1 ± 0.17 µM 30 minutes after a 3 mg/kg dose and a brain to plasma ratio of 0.7 at 30 minutes and 0.9 at 60 minutes.
CVN45502 fully inhibits the intracellular calcium released in cells expressing Hcrtr1 in response to orexin A with IC50 of 0.02 uM.
CVN45502 (30 mg/kg) ameliorates energy-balance defects after DIO in mice, does not show an alteration of total sleep time or locomotor activity.
CVN45502 (30 mg/kg) leads to a reduction in food intake with no major changes in energy expenditure in leptin deficient genetic obese ob/ob mice.