CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H3 receptor (H3R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H3R was demonstrated in radioligand binding displacement assays in rat brain membranes (Ki 2.7 0.3 nM) and recombinant rat and human H3R-expressing systems (Ki 7.2 0.4 and 2.0 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [S]guanosine 5 -O-( -thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H3R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC50 0.1 0.003 mg/kg), and antagonism of the H3R agonist R-methylhistamineinduced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED50 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H3R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.