title: Synthesis and pharmacological characterization of a series of leukotriene analogues with antagonist and agonist activities.
abstract: The synthesis and biological characterization of a series of novel leukotriene antagonists and agonists are reported. All of these compounds are derivatives of (5S,6R,7Z)-5-hydroxy-6-mercapto-9-phenyl-7-nonenoic acid. One of the more potent compounds is (5S,6R,7Z)-6-[[(4-carboxy-2-methoxyphenyl)methyl]thio]-5-hydroxy-9 -(4- heptylphenyl)-7-nonenoic acid (3f). In vitro evaluation of this compound on guinea pig trachea revealed that it is a competitive antagonist of LTD4 and LTE4 with pKB values of 6.4 and 5.8, respectively. On guinea pig ileum, the pKB values obtained for it with LTD4 and E4 were both 7.2. The selectivity of 3f was shown by its lack of effect on carbachol, histamine, and barium chloride concentration-response curves in guinea pig trachea.
authors.affiliation: Department of Medicinal Chemistry, Stuart Pharmaceuticals, Wilmington, Delaware 19897.
authors.forename: P R
authors.initials: PR
authors.lastname: Bernstein
authors.forename: E P
authors.initials: EP
authors.lastname: Vacek
authors.forename: E J
authors.initials: EJ
authors.lastname: Adams
authors.forename: D W
authors.initials: DW
authors.lastname: Snyder
authors.forename: R D
authors.initials: RD
authors.lastname: Krell
mesh_terms: D000818:Animals; D001464:Barium / Q000494:pharmacology; D017609:Barium Compounds; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007526:Isoelectric Point; D017999:Leukotriene E4; D009130:Muscle, Smooth / Q000187:drug effects; D013189:SRS-A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects
chemical_list: D017609:Barium Compounds; D002712:Chlorides; D013189:SRS-A; C024986:barium chloride; D001464:Barium; D017999:Leukotriene E4; D006632:Histamine; D002217:Carbachol