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Vol. 295, Issue 1, 373-381, October 2000

Nonpeptide Tachykinin Receptor Antagonists. II. Pharmacological and Pharmacokinetic Profile of SB-222200, a Central Nervous System Penetrant, Potent and Selective NK-3 Receptor Antagonist

Henry M. Sarau, Don E. Griswold, Brian Bush, William Potts, Punam Sandhu, Dave Lundberg, James J. Foley, Dulcie B. Schmidt, Edward F. Webb, Lenox D. Martin, Jeffrey J. Legos, Robert G. Whitmore, Frank C. Barone, Andrew D. Medhurst, Mark A. Luttmann, Giuseppe A. M. Giardina and Douglas W. P. Hay

The Departments of Pulmonary Biology (H.M.S., D.E.G., J.J.F., D.B.S., E.F.W., L.D.M., M.A.L., D.W.P.H.), Drug Metabolism and Pharmacokinetics (B.B., W.P., P.S., D.L.), and Cardiovascular Biology (J.J.L., R.G.W., F.C.B.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania; the Department of Neuroscience Research (A.D.M.), SmithKline Beecham Pharmaceuticals, Harlow, Essex, United Kingdom; and the Department of Medicinal Chemistry (G.A.M.G.), SmithKline Beecham Pharmaceuticals, Via Zambeletti, Milan, Italy

The pharmacological and pharmacokinetic profile of SB-222200 [(S)-(-)-N-(alpha -ethylbenzyl)-3-methyl-2-phenylquinoline-4-carboxamide], a human NK-3 receptor (hNK-3R) antagonist, was determined. SB-222200 inhibited 125I-[MePhe7]neurokinin B (NKB) binding to Chinese hamster ovary (CHO) cell membranes stably expressing the hNK-3 receptor (CHO-hNK-3R) with a Ki = 4.4 nM and antagonized NKB-induced Ca2+ mobilization in HEK 293 cells stably expressing the hNK-3 receptor (HEK 293-hNK-3R) with an IC50 = 18.4 nM. SB-222200 was selective for hNK-3 receptors compared with hNK-1 (Ki > 100,000 nM) and hNK-2 receptors (Ki = 250 nM). In HEK 293 cells transiently expressing murine NK-3 receptors (HEK 293-mNK-3R), SB-222200 inhibited binding of 125I-[MePhe7]NKB (Ki = 174 nM) and antagonized NKB (1 nM)-induced calcium mobilization (IC50 = 265 nM). In mice oral administration of SB-222200 produced dose-dependent inhibition of behavioral responses induced by i.p. or intracerebral ventricular administration of the NK-3 receptor-selective agonist, senktide, with ED50 values of approximately 5 mg/kg. SB-222200 effectively crossed the blood-brain barrier in the mouse and rat. The inhibitory effect of SB-222200 against senktide-induced behavioral responses in the mouse correlated significantly with brain, but not plasma, concentrations of the compound. Pharmacokinetic evaluation of SB-222200 in rat after oral administration (8 mg/kg) indicated sustained plasma concentrations (Cmax = about 400 ng/ml) and bioavailability of 46%. The preclinical profile of SB-222200, demonstrating high affinity, selectivity, reversibility, oral activity, and central nervous system penetration, suggests that it will be a useful tool compound to define the physiological and pathophysiological roles of NK-3 receptors, in particular in the central nervous system.

0022-3565/00/2951-0373$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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