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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Pharmacological Characterization of the Novel Histamine H3-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

Robbie L. Mcleod, Charlie A. Rizzo, Robert E. West Jr., Robert Aslanian, Kevin Mccormick, Matthew Bryant, Yunsheng Hsieh, Walter Korfmacher, Garfield G. Mingo, LoriAnn Varty, Shirley M. Williams, Neng-Yang Shih, Robert W. Egan and John A. Hey
Journal of Pharmacology and Experimental Therapeutics June 2003, 305 (3) 1037-1044; DOI: https://doi.org/10.1124/jpet.103.049254
Robbie L. Mcleod
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Charlie A. Rizzo
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Robert E. West Jr.
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Robert Aslanian
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Kevin Mccormick
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Matthew Bryant
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Yunsheng Hsieh
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Walter Korfmacher
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Garfield G. Mingo
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LoriAnn Varty
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Shirley M. Williams
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Neng-Yang Shih
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Robert W. Egan
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John A. Hey
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Abstract

We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor antagonist, N-(3,5-dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The H3-receptor binding Ki values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The Ki values for SCH 79687 at histamine H1 and H2 receptors were greater than 1 μM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H3 receptor over α2A-adrenoceptors and imidazoline I2, and >500-fold H3 selectivity compared with over 60 additional receptors. The pA2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 ± 0.3. Similar H3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pKb = 9.4 ± 0.3 and 10.1 ± 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFS-induced contractions in HSV. SCH 79687 (ED50 = 0.3 mg/kg i.v.) attenuated (R)-α-methylhistamine inhibition of sympathetic hypertensive responses in the GP. At the time of activity evaluation, the GP plasma SCH 79687 concentration was 25 ng/ml at the dose of 0.3 mg/kg i.v. In feline nasal studies, combined administration of SCH 79687 (3 mg/kg i.v.) and the H1-antagonist loratadine (3 mg/kg i.v.), at individual doses that do not produce decongestion, inhibited the compound 48/80-induced congestion by 47%. The α-adrenergic agonist phenylpropanolamine (PPA; 1 mg/kg i.v.) also attenuated compound 48/80 nasal responses by 42%. Unlike the H3/H1 combination that did not affect blood pressure (BP), PPA (1 mg/kg i.v.) significantly increased BP compared with control animals by a maximum of 31 mm Hg. Orally, SCH 79687 (10 mg/kg) plus loratadine (10 mg/kg) also produced decongestion without effects on BP. In pharmacokinetic studies, oral dosing with SCH 79687 in the rat (10 mg/kg) and monkey (3 mg/kg) achieved plasma Cmax and area under the curve values greater than 1.5 and 12.1 μg · h/ml, respectively. SCH 79687 is an orally active H3 antagonist with a good pharmacokinetic profile that, in combination with an H1 antagonist, demonstrates decongestant efficacy comparable with oral sympathomimetic decongestants but without hypertensive liabilities.

Footnotes

  • ↵ 1 Current address: Pharmacokinetics and Drug Metabolism, Bayer Corporation, West Haven, CT 06516.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.049254.

  • ABBREVIATIONS: CNS, central nervous system; SCH 79687, N-(3,5-dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea; DMSO, dimethyl sulfoxide; GPI, guinea pig ileum; HSV, human saphenous vein; EFS, electrical field stimulation(ed); HPLC-API/MS/MS, high-performance liquid chromatography-atmospheric pressure ionization tandem mass spectrometry; PK, pharmacokinetic; PPA, phenylpropanolamine.

    • Received January 21, 2003.
    • Accepted March 7, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 3
1 Jun 2003
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Pharmacological Characterization of the Novel Histamine H3-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

Robbie L. Mcleod, Charlie A. Rizzo, Robert E. West, Robert Aslanian, Kevin Mccormick, Matthew Bryant, Yunsheng Hsieh, Walter Korfmacher, Garfield G. Mingo, LoriAnn Varty, Shirley M. Williams, Neng-Yang Shih, Robert W. Egan and John A. Hey
Journal of Pharmacology and Experimental Therapeutics June 1, 2003, 305 (3) 1037-1044; DOI: https://doi.org/10.1124/jpet.103.049254

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Pharmacological Characterization of the Novel Histamine H3-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

Robbie L. Mcleod, Charlie A. Rizzo, Robert E. West, Robert Aslanian, Kevin Mccormick, Matthew Bryant, Yunsheng Hsieh, Walter Korfmacher, Garfield G. Mingo, LoriAnn Varty, Shirley M. Williams, Neng-Yang Shih, Robert W. Egan and John A. Hey
Journal of Pharmacology and Experimental Therapeutics June 1, 2003, 305 (3) 1037-1044; DOI: https://doi.org/10.1124/jpet.103.049254
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