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.

Structure-Activity Relationships of KATP Channel Openers

“…activities for 1,4-benzothiazines such as 20 both in vitro and in vivo. Recently novel 1,4-benzothiazine KCOs such as 21 with vasodilator potencies on rat aortic rings in the subnanomolar range were described [40].…”

From Cromakalim to Different Structural Classes of KATP Channel Openers

“…(14). The replacement of the pyran ring with a thiazine ring was extensively investigated by Cecchetti et al by synthesizing a large series of 1,4-benzothiazines, variously functionalized at the N-4, C-6 and C-2 positions [106,107]. In addition to trying to find a new K ATP CO chemotype, this modification was chosen based on previous reports about the antihypertensive properties shown by simple 1,4-benzothiazine derivatives [108].…”

Role of 1,4-Benzothiazine Derivatives in Medicinal Chemistry

“…The study on 1,4-BT nucleus was amplified by Cecchetti et al who suitably functionalized the nucleus with an electron-withdrawing group at C-6 position and lactam rings, acyclic amides, cyclopentenone, acyl chains, all bearing the usual oxo function at different distances from the 1,4-BT nucleus, as N-4 substituents [45]. All compounds were tested for vasorelaxing activity in vitro compared to levocromakalim, the biologically active enantiomer of cromakalim.…”