Synthesis and smooth muscle relaxant activity of a new series of potassium channel activators: 3-amido-1,1-dimethylindan-2-ols

• Published in: Journal of medicinal chemistry Vol. 34; no. 3; pp. 919 - 926
• Main Authors: Buckle, Derek R, Arch, Jonathan R. S, Edge, Colin, Foster, Keith A, Houge-Frydrych, Catherine S. V, Pinto, Ivan L, Smith, David G, Taylor, John F, Taylor, Stephen G
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-03-1991
• Subjects: activation; Amides - chemical synthesis; Amides - pharmacology; Animals; Benzopyrans - pharmacology; Bronchi - drug effects; Bronchi - physiology; Bronchodilator Agents; channels; Chemical Phenomena; Chemistry; Cromakalim; derivatives; dimethylindanol; Exact sciences and technology; Guinea Pigs; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Indans - chemical synthesis; Indans - pharmacology; induction; Male; Molecular Structure; Muscle Relaxation - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Organic chemistry; Parasympatholytics - chemical synthesis; Parasympatholytics - pharmacology; potassium; Potassium Channels - drug effects; Potassium Channels - physiology; Preparations and properties; Pyrroles - pharmacology; relaxation; smooth muscle; Stereoisomerism; Structure-Activity Relationship; Trachea - drug effects; Trachea - physiology; Bicyclic compound; Aromatic compound; Secondary alcohol; Nitrogen heterocycle; Biological activity; Lactam
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00107a008

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.