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Pharmacological characterization of the novel histamine H3-receptor antagonist N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687).
J Pharmacol Exp Ther. 2003 Jun; 305(3):1037-44.JP

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 microM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H3 receptor over alpha 2A-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)-alpha-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 alpha-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 microg. 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.

Authors+Show Affiliations

Allergy, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033-0539,USA. robbie.mcleod@spcorp.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12649305

Citation

McLeod, Robbie L., et al. "Pharmacological Characterization of the Novel Histamine H3-receptor Antagonist N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)." The Journal of Pharmacology and Experimental Therapeutics, vol. 305, no. 3, 2003, pp. 1037-44.
McLeod RL, Rizzo CA, West RE, et al. Pharmacological characterization of the novel histamine H3-receptor antagonist N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). J Pharmacol Exp Ther. 2003;305(3):1037-44.
McLeod, R. L., Rizzo, C. A., West, R. E., Aslanian, R., McCormick, K., Bryant, M., Hsieh, Y., Korfmacher, W., Mingo, G. G., Varty, L., Williams, S. M., Shih, N. Y., Egan, R. W., & Hey, J. A. (2003). Pharmacological characterization of the novel histamine H3-receptor antagonist N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The Journal of Pharmacology and Experimental Therapeutics, 305(3), 1037-44.
McLeod RL, et al. Pharmacological Characterization of the Novel Histamine H3-receptor Antagonist N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). J Pharmacol Exp Ther. 2003;305(3):1037-44. PubMed PMID: 12649305.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological characterization of the novel histamine H3-receptor antagonist N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). AU - McLeod,Robbie L, AU - Rizzo,Charlie A, AU - West,Robert E,Jr AU - Aslanian,Robert, AU - McCormick,Kevin, AU - Bryant,Matthew, AU - Hsieh,Yunsheng, AU - Korfmacher,Walter, AU - Mingo,Garfield G, AU - Varty,LoriAnn, AU - Williams,Shirley M, AU - Shih,Neng-Yang, AU - Egan,Robert W, AU - Hey,John A, Y1 - 2003/03/20/ PY - 2003/3/22/pubmed PY - 2003/7/8/medline PY - 2003/3/22/entrez SP - 1037 EP - 44 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 305 IS - 3 N2 - 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 microM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H3 receptor over alpha 2A-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)-alpha-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 alpha-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 microg. 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12649305/Pharmacological_characterization_of_the_novel_histamine_H3_receptor_antagonist_N__35_dichlorophenyl__N'_[[4__1H_imidazol_4_ylmethyl_phenyl]_methyl]_urea__SCH_79687__ DB - PRIME DP - Unbound Medicine ER -