1,3,6-trisubstituted indoles as peptidoleukotriene antagonists: benefits of a second, polar, pyrrole substituent.
1,6-Substituted and 3,5-substituted indoles and indazoles containing acylamino and N-arylsulfonyl amide appendages are potent antagonists of the peptidoleukotrienes LTD4 and LTE4. A compound from the 3,5-substituted indole series, N-[4-[[5-[[(cyclopentyloxy)carbonyl]amino]-1-methylindol- 3-yl]methyl]-3-methoxybenzoyl]-2-methyl-benzenesulfonamide (ICI 204,219), is undergoing clinical evaluation for asthma. Two new elements of structural diversity were introduced to this series of antagonists. An investigation of pyrrole substituents in the 1,6-substituted indoles demonstrated that substitution at C-2 was detrimental to biological activity, but the incorporation of hydrophilic groups at C-3 was beneficial. The introduction of a propionamide moiety at C-3 enhanced activity by 1 order of magnitude; N-[4-[[6-(cyclopentylacetamido)-3-[2-(N- methylcarbamoyl)ethyl]indol-1-yl]methyl]-3-methoxy- benzoyl]benzenesulfonamide (15c) has a pKB of 10.7 at the LTD4 receptor on guinea pig trachea. Modifications of the acylamino portion of the disubstituted antagonists demonstrated that a transposition of the amide CO and NH atoms was viable. N-Cyclopentylmethyl amides in both the 1,6- and 3,5-disubstituted indole series were 1 order of magnitude less potent than the corresponding cyclopentylacetamides. In both series this potency loss could be regained by the incorporation of a propionamide substituent at either C-3 or N-1, respectively. For example, N-[4-[[6-[N-(cyclopentylmethyl)carbamoyl]-3-[2-(pyrrolidin-1 - methylbenzenesulfonamide (39c) has a pKB of 9.5.
Brown
F J
FJ
Department of Medicinal Chemistry, ICI Americas Inc., Wilmington, Delaware 19897.
Cronk
L A
LA
Aharony
D
D
Snyder
D W
DW
D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D017999:Leukotriene E4; D008168:Lung / Q000187:drug effects; D008297:Male; D011758:Pyrroles / Q000737:chemistry*; D011869:Radioligand Assay; D011971:Receptors, Immunologic / Q000378:metabolism; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects
D007211:Indoles; D011758:Pyrroles; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D017999:Leukotriene E4