title: Highly potent 1,4-benzothiazine derivatives as K(ATP)-channel openers.
abstract: 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.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy. viola@unipg.it
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Enrica
authors.initials: E
authors.lastname: Filipponi
authors.forename: Lara
authors.initials: L
authors.lastname: Testai
authors.forename: Roberto
authors.initials: R
authors.lastname: Spogli
authors.forename: Enrica
authors.initials: E
authors.lastname: Martinotti
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Fravolini
mesh_terms: 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
chemical_list: 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