Synthesis and biological activity of spirocyclic benzopyran imidazolone potassium channel openers

• Published in: Journal of medicinal chemistry Vol. 36; no. 10; pp. 1480 - 1487
• Main Authors: Gadwood, Robert C, Kamdar, Bharat V, Dubray, Loretta A. Cipkus, Wolfe, Mark L, Smith, Michael P, Watt, William, Mizsak, Stephen A, Groppi, Vincent E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.05.1993; Amer Chemical Soc
• Subjects: Animals; Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - pharmacology; Chemistry; Chemistry, Medicinal; Condensed matter: structure, mechanical and thermal properties; Cromakalim; Exact sciences and technology; Female; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Life Sciences & Biomedicine; Membrane Potentials - drug effects; Muscle, Smooth, Vascular - drug effects; Organic chemistry; Organic compounds; Parasympatholytics - chemistry; Parasympatholytics - pharmacology; Pharmacology & Pharmacy; Physics; Potassium Channels - drug effects; Preparations and properties; Pyrroles - chemistry; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; Science & Technology; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure of solids and liquids; crystallography; Structure of specific crystalline solids; Structure-Activity Relationship; ANTIHYPERTENSIVE ACTIVITY; ACTIVATORS; GUANIDINES; DERIVATIVES; CROMAKALIM; Agonist; Molecular structure; Nitrogen heterocycle; Ionic channel; Guanidines; Tautomerism; Experimental study; Oxygen heterocycle; X ray diffraction; Biological activity; Alkylation; Spiran; Amination; Bicyclic compound; Potassium; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00062a022

A series of novel spirocyclic benzopyran imidazolones were synthesized as rigid analogues of cromakalim. These compounds cause a dose-dependent membrane hyperpolarization of A10 rat aorta cells. This hyperpolarization was blocked by pretreatment with glyburide, indicating that the spirocyclic benzopyran imidazolones were acting by increasing the open probability of ATP-sensitive potassium channels in A10 cells. Representative compounds also showed potent in vivo activity as hypotensive agents in normotensive rats. Many of the compounds described are much more potent than cromakalim both in vitro and in vivo, with one of the most potent compounds being 2,3-dihydro-2,2-dimethyl-6-nitro-2'-(propylamino)spiro[4H-1-benzopyran-4,4'-[4H]imidazol]-5'(1'H)-one (5r). It is concluded that the N1' nitrogen of the imidazolone is an effective substitute for the carbonyl oxygen of cromakalim. The rigid spirocyclic ring fusion holds this nitrogen in an optimum orientation relative to the benzopyran ring.