Irdabisant hydrochloride (CEP-26401) is a selective, orally active, and blood-brain barrier (BBB) penetrant histamine H3 receptor (H3R) inverse agonist/inverse agonist, demonstrating high affinity with K*i values of 7.2 nM and 2.0 nM for rat and human H3R respectively. It exhibits relatively low hERG current inhibitory activity, with an IC*50 of 13.8 μM. This compound has been shown to enhance cognition and promote wakefulness in rat social recognition models, suggesting potential applications in schizophrenia or cognitive impairment research.

Irdabisant (CEP-26401, compound 8a) shows antagonist activity with K b, app values of 1.0 nM and 0.4 nM for rat H3R and human H3R, respectively; shows inverse agonist activity with EC 50 values of 2.0 nM and 1.1 nM for rat H3R and human H3R, respectively [1]. Irdabisant has moderate activity at Muscarinic M 2 (K i = 3.7 ± 0.0 μM) and Adrenergic α 1A (K i = 9.8 ± 0.3 μM) receptors, Dopamine transporters (K i = 11 ± 2 μM), Norepinephrine transporters (K i = 10 ± 1 μM), and phosphodiesterase PDE3 (IC 50 = 15 ± 1 μM) [1]. Irdabisant inhibits the cytochrome P450 enzymes CYP1A2, 2C9, 2C19, 2D6, and 3A4 with IC 50 values of greater than 30 μM, indicating less potential for drug-drug interactions [1].

CEP-26401 (0.01-0.3 mg/kg; p.o.; single dosage) dose-dependently inhibits H3R agonist RAMH -induced dipsogenia [1]. CEP-26401 (0.0001-0.1 mg/kg; i.v. or p.o.; single dosage) improves performance in the rat social recognition model of short-term memory [1]. CEP-26401 (3-30 mg/kg; p.o.; single dosage) exhibits wake-promoting activity in rat [2]. CEP-26401 (3-30 mg/kg; i.p.) increases prepulse inhibition (PPI) in DBA/2NCrl mice [2]. CEP-26401 (1 mg/kg for i.v. and 3 mg/kg for p.o.; single dosage) is rapidly absorbed with high oral bioavailability in rat and monkey, and shows a moderate clearance in monkey and dog compared to the rat [1]. Pharmacokinetic Parameters of Irdabisant (compound 8a) in rats, dogs and monkeys [1]. Rat Dog Monkey i.v. t 1/2 (h) 2.6 2.9 5.4 i.v. V d (L/kg) 9.4 3.5 ± 1.1 3.8 ± 0.9 i.v. CL (mL/min/kg) 42 13.2 ± 1.5 7.7 ± 1.8 p.o. t 1/2 (L/kg) 2.9 2.7 5.0 p.o. AUC (ng·h/mL) 984 1190 ± 180 1919 ± 611 p.o. C max (ng/mL) 270 230 ± 70 760 ± 74 p.o. F (%) 83 22 ± 2 83 ± 18 Brain to plasma ratio 2.6 ± 0.2 2.4 ± 0.4 / Animal Model: Male Sprague-Dawley rats (i.p. 10 mg/kg RAMH-induced dipsogenia model) [1] Dosage: 0.01-0.3 mg/kg Administration: p.o.; single dosage Result: Dose-dependently inhibited H3R agonist RAMH -induced dipsogenia (which manifests as water drinking) with an EC 50 value of 0.06 mg/kg. Animal Model: Male Sprague-Dawley rats (adult rats were briefly exposed to a juvenile rat for build social recognition model) [2] Dosage: 0.0001, 0.001, 0.01 and 0.1 mg/kg for i.p.; 0.01 and 0.1 mg/kg for p.o. Administration: i.v. or p.o.; single dosage Result: Effectively reduced the ratio of investigation duration (RID) at doses over the range from 0.001 to 0.1 mg/kg i.p. and at 0.01 and 0.1 mg/kg p.o., demonstrating potent enhancement of short-term sensory memory in this model. Animal Model: Male Sprague-Dawley rats [2] Dosage: 3, 10 and 30 mg/kg Administration: p.o.; single dosage Result: Exhibited robust wake promotion with the treated animals awake 90% of the time up to 3 h postdosing at 30 mg/kg. Animal Model: Male Sprague-Dawley rats, male beagle dogs and male cynomolgus monkeys [1] Dosage: 1 mg/kg for i.v. and 3 mg/kg for p.o. Administration: i.v. and p.o. Result: Exhibited rapid absorption with high oral bioavailability in rat and monkey, and showed a moderate clearance in monkey and dog compared to the rat. Animal Model: Male DBA/2NCrl mice (19-27 g; 7-9 weeks) [2] Dosage: 3, 10 and 30 mg/kg Administration: i.p.; single dosage Result: Increased prepulse inhibition (PPI) in DBA/2NCrl mice, whereas the antipsychotic Risperidone is effective at 0.3 and 1 mg/kg i.p..