Evolution of a series of peptidoleukotriene antagonists: synthesis and structure-activity relationships of 1,6-disubstituted indoles and indazoles.
A perception of structural similarities between two independent series of leukotriene antagonists (one emanating from FPL 55712 and one based upon the leukotrienes themselves) led to the discovery of a novel class of indole and indazole derived antagonists of peptidoleukotrienes. A systematic exploration of C-6 substituted 4-(indol-1-ylmethyl)-3-methoxybenzoic acids identified cyclopentylacetamide and cyclopentylurethane as preferred substituents. The corresponding indazoles were equipotent. These compounds are selective leukotriene antagonists with pKB values of 7.5-7.8 vs LTE4 on guinea pig trachea.
Brown
F J
FJ
Department of Medicinal Chemistry, ICI Pharmaceuticals Group, Wilmington, Delaware 19897.
Yee
Y K
YK
Cronk
L A
LA
Hebbel
K C
KC
Krell
R D
RD
Snyder
D W
DW
D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D007191:Indazoles; D007211:Indoles; D011720:Pyrazoles; D013189:SRS-A