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.
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.
Schou
Søren C
SC
Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
Hansen
Holger C
HC
Tagmose
Tina M
TM
Boonen
Harrie C M
HC
Worsaae
Anne
A
Drabowski
Michael
M
Wahl
Philip
P
Arkhammar
Per O G
PO
Bodvarsdottir
Thora
T
Antoine
Marie-Hélène
MH
Lebrun
Philippe
P
Hansen
John Bondo
JB
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008564:Membrane Potentials / Q000187:drug effects; D009570:Nitriles / Q000138:chemical synthesis* / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000819:agonists*; D013055:Spectrophotometry, Infrared; D013843:Thiazines / Q000138:chemical synthesis* / Q000494:pharmacology*
C500406:4H-1,4-benzothiazine-2-carbonitrile 1,1-dioxide; D000577:Amides; C500407:N-(2-cyanomethylsulfonylphenyl)acylamide; D009570:Nitriles; D015221:Potassium Channels; D013843:Thiazines; D000255:Adenosine Triphosphate