Abstract:
:(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic acid (11, SB 201993) is a novel, potent LTB4 receptor antagonist. Compound 11 arose from a structure-activity study of a series of trisubstituted pyridines that demonstrated LTB4 receptor antagonist activity. The placement of an additional methylene unit in the sulfur containing chain linking the pyridine and benzoic acid moieties of lead compound 8 (K(i) = 80 nM) resulted in a greater than 10-fold increase in receptor affinity. Additionally, in this new series of compounds, the oxidation state of the sulfur was found to be critical to the activity, i.e., the sulfoxide and sulfone showed substantially lower affinity for the LTB4 receptor. Compound 11 competitively inhibits the binding of [3H]LTB4 to LTB4 receptors on human polymorphonuclear leukocytes with a Ki of 7.1 nM and blocks both the LTB4-induced calcium mobilization and the LTB4-induced degranulation responses in these cells with IC50 values of 131 and 271 nM, respectively. Compound 11 demonstrated oral LTB4 antagonist activity as well as topical antiinflammatory activity in the mouse.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Daines RA,Chambers PA,Eggleston DS,Foley JJ,Griswold DE,Haltiwanger RC,Jakas DR,Kingsbury WD,Martin LD,Pendrak Idoi
10.1021/jm00046a017subject
Has Abstract,Author List Incompletepub_date
1994-09-30 00:00:00pages
3327-36issue
20eissn
0022-2623issn
1520-4804journal_volume
37pub_type
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