Hydroxylated Analogues of ATP-Sensitive Potassium Channel Openers Belonging to the Group of 6- and/or 7-Substituted 3-Isopropylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides: Toward an Improvement in Sulfonylurea Receptor 1 Selectivity and Metabolism Stability

Abstract

Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic tissue (compared to vascular smooth muscle tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a.

Direct Activation ofβ-Cell KATPChannels with a Novel Xanthine Derivative

“…Pancreatic K ATP channels are validated drug targets for intractable hypoglycemia due to insulinoma and congenital hyperinsulinism, and therefore considerable efforts have been made to develop specific activators of K ir 6.2/SUR1 channels (Hansen, 2006;Pirotte et al, 2010;de Tullio et al, 2011). Diazoxide is the best-known SUR1-preferring opener and has been used clinically for more than 50 years.…”

“…In an effort to develop openers with fewer side effects, several groups have synthesized analogs from existing lead compounds that show improved potency and selectivity toward K ir 6.2/SUR1. Structural modifications to the diazoxide scaffold have led to several new series with submicromolar potency and selectivity for pancreatic over smooth muscle K ATP channels (Pirotte et al, 2010;de Tullio et al, 2011). One analog, termed NN414 (Dabrowski et al, 2003), shows favorable activity in obese rats (Carr et al, 2003;Alemzadeh et al, 2004), as well as healthy and type 2 diabetes patients (Zdravkovic et al, 2005(Zdravkovic et al, , 2007.…”

Crystal structure of (R)-6′-bromo-3,3-dimethyl-3′,4′-dihydro-2′H-spiro[cyclohexane-1,3′-1,2,4-benzothiadiazine] 1′,1′-dioxide

“…In addition, 2-substituted-2H-1,2,4benzothiadiazine-3(4H)one 1,1-dioxides have been found to exhibit varying degrees of sedative and hypotensive activities (Khelili et al, 2012). A number of benzothiadiazine 1,1dioxide derivatives have recently been reported to display numerous biological activities (Tullio et al, 2011).…”

Molecular and Crystal Structures of Two 1,2,4-Benzothiadiazine Derivatives

“…2-Substituted-2H-1,2,4-benzothiadiazine-3(4H)one 1,1-dioxides showed varying degrees of sedative and hypotensive activities [ 15 ]. A number of benzothiadiazine 1,1-dioxide derivatives have recently been reported to display numerous biological activities [16][17][18][19][20][21][22]. A literature search reveals © Kumar P.P.S., Suchetan P.A., Sreenivasa S., Naveen S., Lokanath N.K., Kumar D.B.A., 2015 that 1,2,4-benzothiadiazine 1,1-dioxides are generally synthesized either by condensation of o-amino benzene sulfonamides with urea at elevated temperatures [ 23 ] or by the reaction of o-amino benzene sulfonamide with isocyanates in DMF under reflux [ 24 ].…”