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Synthesis and pharmacological evaluation of 4H-1,4-benzothiazine-2-carbonitrile 1,1-dioxide and N-(2-cyanomethylsulfonylphenyl)acylamide derivatives as potential activators of ATP sensitive potassium channels.

par Schou, Søren C;Hansen, Holger C;Tagmose, Tina M;Boonen, Harrie C M;Worsaae, Anne;Drabowski, Michael;Wahl, Philip;Arkhammar, Per O G;Bodvarsdottir, Thora;Antoine, Marie-Hélène ;Lebrun, Philippe ;Hansen, John Bondo
Référence Bioorganic & medicinal chemistry, 13, 1, page (141-155)
Publication Publié, 2005-01

Article révisé par les pairs

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Résumé :

1,2,4-Thiadiazine derivatives, like 3-methyl-7-chlorobenzo-4H-1,2,4-thiadiazine 1,1-dioxide, diazoxide and 7-chloro-3-isopropylamino-4H-benzo-1,2,4-thiadiazine 1,1-dioxide, BPDZ 73, are potent openers of Kir6.2/SUR1 K(ATP) channels. To explore the structure-activity relationship of this series of K(ATP) openers, 4H-1,4-benzothiazine-2-carbonitrile 1,1-dioxide and N-(2-cyanomethylsulfonylphenyl)acylamide derivatives were synthesized from 2-acetylamino-5-chloro-benzenesulfonic acid pyridinium salt or 2-aminobenzenethiols. The 4H-1,4-benzothiazine-2-carbonitrile 1,1-dioxide derivatives (e.g., 7-chloro-3-isopropylamino-4H-1,4-benzothiazine-2-carbonitrile 1,1-dioxide, 3f) were found to activate K(ATP) channels as indicated by their ability to hyperpolarize beta cell membrane potential, to inhibit glucose-stimulated insulin release in vitro and to increase ion currents through Kir6.2/SUR1 channel as measured by patch clamp. The potency and efficacy of, for example, 3f is however significantly reduced compared to the corresponding 4H-1,2,4-benzothiadiazine 1,1-dioxide derivatives. Opening of the 4H-1,2,4-thiadiazine ring to get (e.g., 2-cyanomethylsulfonyl-4-fluorophenyl) carbamic acid isopropyl ester (4c) gives rise to compounds, which are able to open K(ATP) channels but with considerable reduced potency compared to, for example, diazoxide. Compound 3a, 7-chloro-3-methyl-4H-1,4-benzothiazine-2-carbonitrile 1,1-dioxide, which inhibits insulin release in vitro from beta cells and rat islets, reduces plasma insulin levels and blood pressure in anaesthetized rats upon intravenous administration.