Substituted 3-(phenylmethyl)-1H-indole-5-carboxamides and 1-(phenylmethyl)indole-6-carboxamides as potent, selective, orally active antagonists of the peptidoleukotrienes.
Substituted indole-5-carboxamides and indole-6-carboxamides have been found to be potent and selective antagonists of the peptidoleukotrienes. Initial derivatives of these series (4-[[5-[(cyclopentylmethyl)carbamoyl]-1-methylindol-3-yl] methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide (5a) and 4-[[6-[(cyclopentylmethyl)carbamoyl]-3-methylindol-1-yl] methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide (6a), respectively), when compared to the corresponding indole amides (e.g. 28 and 29), were found to be approximately 10-fold less potent in vitro and substantially less active when administered orally to guinea pigs. Efforts to improve the potency of the title series by variation of the amide, indole, or sulfonamide substituents led to compounds of comparable in vitro potency to ICI 204,219, but of somewhat lower oral activity. A trend which suggested that more lipophilic transposed amides were needed to increase oral activity was exploited with some success and has led to the discovery of 5q (4-[[5-[(2-ethylbutyl)-carbamoyl]-1-ethylindol-3-yl]methyl]- 3- methoxy-N-[(2-methylphenyl)sulfonyl]benzamide), a transposed amide with subnanomolar affinity for the leukotriene receptor and an oral ED50 of 5 mg/kg in a model of asthma in guinea pigs. In this model, ICI 204,219 was active at 0.4 mg/kg. The absolute bioavailability of 5q has been found to be 28% in the rat, as compared to 68% for ICI 204,219, with significant levels of 5q observed in the blood of rats up to 24 h postdose.
Department of Medicinal Chemistry, ICI Pharmaceuticals Group, Business Unit of ICI Americas Inc., Wilmington, Delaware 19897.
R T
RT
Jacobs
F J
FJ
Brown
L A
LA
Cronk
D
D
Aharony
C K
CK
Buckner
E J
EJ
Kusner
K M
KM
Kirkland
K L
KL
Neilson
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017999:Leukotriene E4; D008168:Lung / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; 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
D000577:Amides; D007211:Indoles; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D017999:Leukotriene E4