title: Azulene derivatives as TXA2/PGH2 receptor antagonists--II. Synthesis and biological activity of 6-mono- and 6-dihydroxylated-isopropylazulenes.
abstract: In order to examine the correlation between activity and hydrophilicity of the side chain of sodium 3-[4-(4-chlorobenzenesulfonylamino)butyl]-6-isopropylazulene -1-sulfonate (KT2-962), a non-prostanoid TXA2/PGH2 receptor antagonist, one or two hydroxyl groups were introduced into the isopropyl moiety. A series of 6-hydroxylated-isopropylazulenes were synthesized by regioselective oxidation of 6-isopropylazulenes and their in vitro and in vivo antagonistic activities were studied. Both the primary and tertiary alcohols, monohydroxylated derivatives, exhibited potent biological activities comparable to unmodified 6-isopropylazulenes both in vitro and in vivo. In contrast, the activities of 1,2- and 1,3-diols of 6-substituted derivatives, markedly decreased, but recovered by O-isopropylidenation of the dihydroxyl moiety. These findings indicate that the moderate hydrophobicity of substituent at the 6-position of the azulene ring might be required for the activity and the size of the substituent at this position, not so rigid for keeping potent biological activity.
authors: Kotobuki Research Laboratories, Kotobuki Seiyaku Company, Ltd, Nagano, Japan.
authors: M
authors: M
authors: Yokota
authors: S
authors: S
authors: Uchibori
authors: H
authors: H
authors: Hayashi
authors: R
authors: R
authors: Koyama
authors: K
authors: K
authors: Kosakai
authors: S
authors: S
authors: Wakabayashi
authors: T
authors: T
authors: Tomiyama
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology*; D052176:Azulenes; D001557:Benzenesulfonates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D003508:Cycloheptanes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D003645:Death, Sudden / Q000209:etiology; D006801:Humans; D008297:Male; D051379:Mice; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011463:Prostaglandins H / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052176:Azulenes; D001557:Benzenesulfonates; D003508:Cycloheptanes; D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C080458:6-isopropyl-3-(4-(4-chlorobenzenesulfonylamino)butyl)azulene-1-sulfonic acid sodium salt; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C005525:azulene