Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene receptor antagonists. 1. Initial structure-activity relationships
| Autor: | Johnson Wh, Chan Wk, Magnien E, Galemmo Ra, Lin Cj, Raymond D. Youssefyeh, Fu-Chih Huang, Tan J, Campbell Hf, Lee Td |
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| Rok vydání: | 1990 |
| Předmět: |
Azoles
Chemical Phenomena Stereochemistry Guinea Pigs Receptors Leukotriene B4 Tetrazoles Guinea pig Structure-Activity Relationship Oral administration Drug Discovery medicine Animals Moiety Potency Receptors Immunologic Lung ED50 Leukotriene Chemistry Phenyl Ethers Antagonist respiratory system Bronchodilator Agents Hydroxyquinolines Quinolines Leukotriene Antagonists Molecular Medicine Bronchoconstriction medicine.symptom |
| Zdroj: | Journal of Medicinal Chemistry. 33:1186-1194 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00166a016 |
| Popis: | This series of reports describes the development of orally active, highly potent, specific antagonists of the peptidoleukotrienes containing a (2-quinolinylmethoxy)phenyl moiety. Described in this first report are the structure-activity relationships that led to a more than a 20-fold improvement of the potency and selectivity of the initial chemical lead (RG 5901). From this series of compounds, RG 7152 (16) was identified and selected for further evaluation in the clinic as an antiasthmatic agent. Compound 16 competitively inhibits [3H]LTD4 binding to membranes from guinea pig lung (Ki = 38 +/- 6 nM) and the spasmogenic activity of LTC4, LTD4, and LTE4 in parenchymal lung strips from guinea pigs. Unlike the original lead (RG 5901), compound 16 does not inhibit 5-lipoxygenase from guinea pig PMNs. Following oral administration to guinea pigs, 16 blocks LTD4-induced dermal permeability (ED50 = 6.9 mg/kg), LTD4-induced bronchoconstriction (ED50 = 1.1 mg/kg), antigen-induced bronchoconstriction (ED50 = 2.5 mg/kg), and anaphylactic-induced mortality (ED50 = 16 mg/kg). These studies on structure-activity relationships indicate that there is a requirement for an acidic function and the presence of the (2-quinolinylmethoxy)phenyl moiety in a specific geometric arrangement. |
| Databáze: | OpenAIRE |
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