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Irdabisant (CEP-26401) is a selective, orally active and blood-brain barrier (BBB) penetrant histamine H3 receptor (H3R) inverse agonist/inverse agonist with Ki values of 7.2 nM and 2.0 nM for rat H3R and human H3R, respectively. Irdabisant has relatively low inhibitory activity against hERG current with an IC50 of 13.8 μM. Irdabisant has cognition-enhancing and wake-promoting activities in the rat social recognition model. Irdabisant can be used to research schizophrenia or cognitive impairment[1][2]. | [Definition]
ChEBI: Irdabisant is a ring assembly and a member of pyridazines. | [in vivo]
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. t1/2 (h) | 2.6 | 2.9 | 5.4 | | i.v. Vd (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. t1/2 (L/kg) | 2.9 | 2.7 | 5.0 | | p.o. AUC (ng·h/mL) | 984 | 1190 ± 180 | 1919 ± 611 | | p.o. Cmax (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 (HY-100999)-induced dipsogenia (which manifests as water drinking) with an EC50 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 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 (HY-11018) is effective at 0.3 and 1 mg/kg i.p.. |
| 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. |
| [IC 50]
rat H3 receptor: 7.2 nM (Ki); human H3 receptor: 2 nM (Ki) | [References]
[1] Hudkins RL, et al. Discovery and characterization of 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (CEP-26401, irdabisant): a potent, selective histamine H3 receptor inverse agonist. J Med Chem. 2011 Jul 14;54(13):4781-92. DOI:10.1021/jm200401v
[2] Raddatz R, et al. CEP-26401 (irdabisant), a potent and selective histamine H? receptor antagonist/inverse agonist with cognition-enhancing and wake-promoting activities. J Pharmacol Exp Ther. 2012 Jan;340(1):124-33. DOI:10.1124/jpet.111.186585 |
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