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.

doi:10.1021/jm200786z

Paper

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.

Published Nov 29, 2011 · P. de Tullio, A. Servais, M. Fillet

Journal of medicinal chemistry

Q1 SJR score

24

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0

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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.

In Vitro Study

Study Snapshot

Hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides show improved sulfonylurea receptor 1 selectivity and metabolic stability, making them potential lead candidates for pancreatic tissue treatment.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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.

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