Vol. 281, Issue 3, 1303-1311, 1997

Nonpeptide Tachykinin Receptor Antagonists: I. Pharmacological and Pharmacokinetic Characterization of SB 223412, a Novel, Potent and Selective Neurokinin-3 Receptor Antagonist

Henry M. Sarau, Don E. Griswold, William Potts, James J. Foley, Dulcie B. Schmidt, Edward F. Webb, Lenox D. Martin, Mary E. Brawner, Nabil A. Elshourbagy, Andrew D. Medhurst, Giuseppe A. M. Giardina and Douglas W. P. Hay

Departments of Pulmonary Pharmacology (H.M.S., J.J.F., D.B.S., D.W.P.H.), Immunopharmacology (D.E.G., E.F.W., L.D.M.), Drug Metabolism and Pharmacokinetics (W.P.), Gene Expression Sciences (M.E.B.) and Molecular Genetics (N.A.E.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, 19406, Department of Neurology Research (A.D.M.), SmithKline Beecham Pharmaceuticals, Harlow, Essex, CM19 5AW, UK, and Department of Chemistry (G.A.M.G.), SmithKline Beecham Pharmaceuticals, 20021 Baranzate, Milan, Italy

The in vitro and in vivo pharmacological profile of SB 223412 [(S)-()-N-(-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide], a novel human NK-3 (hNK-3) receptor antagonist, is described. SB 223412 demonstrated enantioselective affinity for inhibition of [¹²⁵I][MePhe⁷]neurokinin B (NKB) binding to membranes of CHO cells expressing the hNK-3 receptor (CHO hNK-3). SB 223412, the (S)-isomer, (K_i = 1.0 nM), has similar affinity as the natural ligand, NKB (K_i = 0.8 nM) and another nonpeptide NK-3 receptor antagonist, SR 142801 (K_i = 1.2 nM). SB 223412 was selective for hNK-3 receptors compared with hNK-1 (>10,000-fold selective) and hNK-2 receptors (>140-fold selective), and selectivity was further demonstrated by its lack of effect, in concentrations up to 1 or 10 µM, in >60 receptor, enzyme and ion channel assays. SB 223412 enantioselectively inhibited the NKB-induced Ca⁺⁺ mobilization in HEK 293 cells stably expressing the hNK-3 receptor. SB 223412 (10-1,000 nM) produced concentration-dependent rightward shifts in NKB-induced Ca⁺⁺ mobilization concentration-response curves with a K_b value of 3 nM. In addition, SB 223412 antagonized senktide-induced contraction in the isolated rabbit iris sphincter muscle (K_b = 1.6 nM). In mice, oral administration of SB 223412 produced dose-dependent inhibition of behavioral responses induced by the NK-3 receptor-selective agonist, senktide (ED₅₀ = 12.2 mg/kg). Pharmacokinetic evaluation of SB 223412 in rat and dog indicated low plasma clearance, oral bioavailability and high and sustained plasma concentrations after 4 to 8 mg/kg oral dosages. The preclinical profile of SB 223412 (high affinity, selectivity, reversibility and oral activity) suggests that it will be a useful tool compound to define the physiological and pathophysiological roles of NK-3 receptors.