[Abstract Title]. - Society for Neuroscience

285. Sleep: Molecular, Cellular and Pharmacology I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 285.4/QQ20
Topic: E.08.c. Sleep: Molecular, cellular, and pharmacology
Title: Characterization of APD916, a novel histamine H3 antagonist with wake promoting
properties
Authors: *A. J. GROTTICK 1 , G. BARRERA 1 , J. EDWARDS 2 , E. HAUSER 1 , H. LAM 4 , J.
LOREA 1 , N. MAIDMENT 4 , V. J. SANTORA 3 , G. SEMPLE 3 , B. M. SMITH 3 , J. M. SMITH 3 ,
M. SUAREZ 1 , B. THOMSEN 1 , K. WHELAN 1 , A. SIEGEL 6,5 , J. M. SIEGEL 6,5 , M.-F. WU 6,5 ,
W. CHEN 2 ;
1 CNS pharmacology, 2 DMPK, 3 Medicinal chemistry, Arena Pharmaceuticals Inc., San Diego,
CA; 4 Dept. Physiol., 5 Dept. Psychiatry, UCLA, Los Angeles, CA; 6 VA GLAHS, Sepulveda, CA
Abstract: APD916 bound H3 receptors across three species with high affinity (rat H3; Ki
=1.2nM, human H3; Ki=4.2nM dog H3; IC50=3.8nM) and displayed greater than 1000-fold
selectivity against a standard panel of >70 reference sites, including the other known histamine
receptors. When assessed in a functional assay, APD916 was a potent and highly efficacious
inverse agonist of the recombinant human receptor (GTPγS binding, IC50=0.7nM). In vivo
pharmacokinetic (PK) studies in the rat demonstrated rapid absorption (Tmax=0.3h), a relatively
short half-life (T½=1-1.5h), good oral bioavailability (%F=27%) and high brain penetrance
(brain/plasma ratio ~2). Functional in vivo efficacy in the rat was established in a
pharmacological screen (blockade of R-α-methylhistamine (RAMH)-induced polydipsia) with a
minimum effective oral dose of 0.3mg/kg. Efficacy in this screen was maintained after ten days
of subchronic dosing. Using the same paradigm, we demonstrated that at twice the minimum
effective dose (0.6mg/kg PO), APD916 was no longer active 6h after administration. EEG
recordings in the rat found APD916 to increase wakefulness (minimum effective oral dose of
0.3mg/kg) without concomitant changes in locomotor activity. These wake promoting properties
of APD916 were more pronounced during the rodent subjective night, and were maintained
throughout five days of dosing. Lastly, when administered to the narcoleptic Doberman,
APD916 significantly reduced both number and total duration of palatable food-induced
cataplectic attacks at one and four hours after administration, an effect which no longer remained
at 24h post-dose. Taken together, these data suggest APD916 to be a potent and selective
antagonist/inverse agonist of histamine H3 receptors across species, with a moderate duration of
action. APD916 may therefore have utility in the treatment of disorders characterized by
excessive daytime sleepiness, including narcolepsy.
Disclosures: A.J. Grottick, Arena Pharmaceuticals, A. Employment (full or part-time); G.
Barrera, None; J. Edwards, Arena Pharmaceuticals, A. Employment (full or part-time); E.
Hauser, Arena Pharmaceuticals, A. Employment (full or part-time); J. Lorea, Arena
Pharmaceuticals, A. Employment (full or part-time); V.J. Santora, Arena Pharmaceuticals, A.
Employment (full or part-time); G. Semple, Arena Pharmaceuticals, A. Employment (full or