ABSTRACT
The synthesis of a novel series of smooth muscle relaxants which have been shown to act via the opening or activation of potassium channels is described. Compounds have been evaluated for their ability to inhibit spontaneous tone in guinea pig isolated trachealis and structure-activity relationships are discussed. One compound in particular, 1,1-dimethyl-5-nitro-3-(2-pyridon-1-yl)indan-2-ol, (16) was identified as a potent relaxant of airways smooth muscle in vitro with IC50 = 0.15 microM and was found to significantly inhibit histamine-induced dyspnoea in conscious guinea pigs when given orally 30-45 min prior to challenge.
Subject(s)
Indans/chemical synthesis , Muscle Relaxation/drug effects , Muscle, Smooth/physiology , Parasympatholytics/chemical synthesis , Potassium Channels/drug effects , Amides/chemical synthesis , Amides/pharmacology , Animals , Benzopyrans/pharmacology , Bronchi/drug effects , Bronchi/physiology , Bronchodilator Agents , Chemical Phenomena , Chemistry , Cromakalim , Guinea Pigs , Indans/pharmacology , Male , Molecular Structure , Muscle, Smooth/drug effects , Parasympatholytics/pharmacology , Potassium Channels/physiology , Pyrroles/pharmacology , Stereoisomerism , Structure-Activity Relationship , Trachea/drug effects , Trachea/physiologyABSTRACT
A series of 4-amido-3,4-dihydro-2H-1-benzopyran-3-ols and 4-amido-2H-1-benzopyrans related to the potassium channel activator cromakalim have been prepared and evaluated for their relaxant activity in guinea pig isolated tracheal spirals. Several analogues show enhanced relaxant activity relative to cromakalim in this preparation and the rank order of potency for those substituents investigated at C-6 was CF3 greater than CN greater than C2H5 greater than aza greater than or equal to CH3. One compound, trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-7-(trifluor omethyl)-2H- 1-benzopyran-3-ol (24), was resolved into its two enantiomers and the activity was shown to reside essentially in the (+)-isomer, adding further support to the suggestion that the smooth muscle receptor for these potassium channel activators is stereoselective.
Subject(s)
Amides/pharmacology , Benzopyrans/pharmacology , Bronchodilator Agents/pharmacology , Muscle Relaxation/drug effects , Pyrroles/pharmacology , Trachea/physiology , Amides/chemical synthesis , Amides/chemistry , Animals , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Bronchodilator Agents/chemical synthesis , Bronchodilator Agents/chemistry , Chemical Phenomena , Chemistry , Cromakalim , Guinea Pigs , Molecular Structure , Potassium Channels/drug effects , Potassium Channels/physiology , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis and structure--activity profile of 2-substituted benzimidazol-4-ols as inhibitors of cell-free RBL-1 5-lipoxygenase are discussed, and their potency is compared with that of the standard inhibitors phenidone, AA 861, BW 755C, and nordihydroguaiaretic acid. In contrast to the standard compounds, most did not inhibit the release of slow-reacting substance of anaphylaxis (SRS-A) in vivo when administered at 200 microM ip to rats subjected to peritoneal anaphylaxis, although five compounds containing a methoxylated benzyl group (compounds 36, 39, 42, and 43) or hydroxylated benzyl group (41) showed similar activity to that of phenidone, nordihydroguaiaretic acid, and AA 861. Of the many compounds tested, two, 5-tert-butyl-7-methyl-2-(trifluoromethyl)-1H-benzimidazol-4-ol (57) and 2-(4-methoxybenzyl)-7-methyl-1H-benzimidazol-4-ol (36), like dexamethasone, inhibited monocyte accumulation in a pleural exudate model of inflammation. Standard lipoxygenase inhibitors such as phenidone, BW 755C, and AA 861 were inactive in this system.
Subject(s)
Arachidonate Lipoxygenases/antagonists & inhibitors , Benzimidazoles/chemical synthesis , Lipoxygenase Inhibitors , Animals , Benzimidazoles/pharmacology , Female , Rats , Rats, Inbred Strains , SRS-A/metabolism , Structure-Activity RelationshipABSTRACT
A short series of the title compounds was prepared and evaluated for antiallergic activity in the rat passive cutaneous anaphylaxis screen. All but the two N-methylated derivatives were active in this screen by the intravenous route, the most potent being the symmetrical dimethyl compound, 4,9-dihydro-6,7-dimethyl-4,9-dioxo-1H-naphtho[2,3-d]-v-triazole, and its 5-nitro derivative. The latter two compounds were noticeably more potent than disodium cromoglycate, and one of these, the unnitrated material, was selected for further evaluation as a potential antiasthmatic drug.
