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

Abstract

Optimization of a novel series of pyridazin-3-one histamine H(3) receptor (H(3)R) antagonists/inverse agonists identified 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (8a, CEP-26401; irdabisant) as a lead candidate for potential use in the treatment of attentional and cognitive disorders. 8a had high affinity for both human (K(i) = 2.0 nM) and rat (K(i) = 7.2 nM) H(3)Rs with greater than 1000-fold selectivity over the hH(1)R, hH(2)R, and hH(4)R histamine receptor subtypes and against an in vitro panel of 418 G-protein-coupled receptors, ion channels, transporters, and enzymes. 8a demonstrated ideal pharmaceutical properties for a CNS drug in regard to water solubility, permeability and lipophilicity and had low binding to human plasma proteins. It weakly inhibited recombinant cytochrome P450 isoforms and human ether-a-go-go-related gene. 8a metabolism was minimal in rat, mouse, dog, and human liver microsomes, and it had good interspecies pharmacokinetic properties. 8a dose-dependently inhibited H(3)R agonist-induced dipsogenia in the rat (ED(50) = 0.06 mg/kg po). On the basis of its pharmacological, pharmaceutical, and safety profiles, 8a was selected for preclinical development. The clinical portions of the single and multiple ascending dose studies assessing safety and pharmacokinetics have been completed allowing for the initiation of a phase IIa for proof of concept.

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

“…Plasma and brain concentrations of CEP-26401 measured in these animals 1 h after oral dosing at 0.1 mg/kg were 6.7 Ϯ 1.0 ng/ml (22 nM) and 19.8 Ϯ 3.8 ng/g (64 nM), respectively. These values are consistent with the previously reported pharmacokinetic properties of CEP-26401 in the rat, including high oral bioavailability (F of 83%) and good brain exposure (brain to plasma ratio of 2.6) (Hudkins et al, 2011).…”

“…35 S]GTP␥S binding at recombinant rH 3 R (K b, app ϭ 1.0 Ϯ 0.2 nM) and hH 3 R (K b, app ϭ 0.4 Ϯ 0.1 nM) (Hudkins et al, 2011). Antagonism was reversed by increasing concentrations of RAMH (data not shown).…”

“…3) was attained at a total brain concentration of 64 nM, 20 times higher than the binding K i value of 2.7 nM determined in rat brain homogenates in vitro. Although CEP-26401 displayed low protein binding in dialysis studies with rat plasma proteins and ϳ40% free fraction when dialyzed with rat brain homogenate (Hudkins et al, 2011), these in vitro measures are estimates and may not reflect the actual free fraction in vivo. In addition, the preparation of brain homogenates and the presence of assay buffer components may affect binding affinities determined in vitro.…”

“…In the present report, the pharmacological properties and behavioral effects of the novel H 3 R antagonist/inverse agonist CEP-26401 [6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one; irdabisant] (Hudkins et al, 2011) (Fig. 1) are described.…”

“…Specific binding was more than 90% of total binding. Plasma and brain samples were collected from the study animals in the ex vivo binding experiments and submitted for quantitative analysis to determine the respective compound concentrations as described previously (Hudkins et al, 2011).…”