104435-96-3Relevant academic research and scientific papers
1,3,6-Trisubstituted indoles as peptidoleukotriene antagonists: Benefits of a second, polar, pyrrole substituent
Brown,Cronk,Aharony,Snyder
, p. 2419 - 2439 (2007/10/02)
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-methoxybenzoyl]benzenesulfonamide (15c) has a pK(B) 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-ylcarbonyl)ethyl]indol-1- yl]methyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide (39c) has a pK(B) of 9.5.
Evolution of a Series of Peptidoleukotriene Antagonists: Synthesis and Structure-Activity Relationships of 1,6-Disubstituted Indoles and Indazoles
Brown, Frederick J.,Yee, Ying K.,Cronk, Laura A.,Hebbel, Kevin C.,Krell, Robert D.,Snyder, David W.
, p. 1771 - 1781 (2007/10/02)
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.
