Highly potent 1,4-benzothiazine derivatives as K(ATP)-channel openers.
A series of 1,4-benzothiazines, suitably functionalized at the N-4 and C-6 positions, arising from the replacement of a benzopyran-based structure of cromakalim with a 1,4-benzothiazine nucleus, has been synthesized as potassium channel openers (KCOs). Most of the tested compounds show high vasorelaxant potency that is considerably higher than that of the reference levcromakalim (LCRK). In the presence of the well-established selective K(ATP) blocker, glibenclamide, the vasorelaxing effects were antagonized in a competitive fashion, indicating the involvement of the K(ATP) channel in their pharmacological effect. Some aspects of the structure-activity relationship associated with the N-4 and C-6 substituents are discussed. The highest level of activity was achieved with a cyclopentenone ring at the N-4 position coupled with an electron-withdrawing group such as nitro, trifluoromethyl, or cyano at the C-6 position. Compounds 4c, 5c, and 6c displayed a vasorelaxant potency at least 10 000 times greater than that of LCRK, thus becoming the most potent KCOs identified to date.
Cecchetti
Violetta
V
Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy. viola@unipg.it
Calderone
Vincenzo
V
Tabarrini
Oriana
O
Sabatini
Stefano
S
Filipponi
Enrica
E
Testai
Lara
L
Spogli
Roberto
R
Martinotti
Enrica
E
Fravolini
Arnaldo
A
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C476983:2,2-dimethyl-4-(1-oxo-2-cyclopenten-2-yl)-6-trifluoromethyl-3,4-dihydro-2H-1,4-benzothiazine; C476982:2,2-dimethyl-6-nitro-4-(1-oxo-2-cyclopenten-2-yl)-3,4-dihydro-2H-1,4-benzothiazine; C476984:6-cyano-2,2-dimethyl-4-(1-oxo-2-cyclopenten-2-yl)-3,4-dihydro-2H-1,4-benzothiazine; D015221:Potassium Channels; D013843:Thiazines; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate