Synthesis and pharmacological evaluation of some N-arylsulfonyl-N-methyl-N′-(2,2-dimethyl-2H-1-benzopyran-4-yl)ureas structurally related to cromakalim

Khelili, Smail; Lebrun, Philippe; Tullio, Pascal De; Pirotte, Bernard

doi:10.1016/j.bmc.2006.01.009

Cited by 10 publications

(5 citation statements)

References 13 publications

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“…Clinical trials were initiated but later suspended due to druginduced elevations of key liver enzymes (Hansen, 2006). Analogs of the SUR2-preferring openers cromakalim and pinacidil that exhibit selectivity for pancreatic K ATP channels (Khelili et al, 2006(Khelili et al, , 2008Sebille et al, 2006Sebille et al, , 2008Florence et al, 2009Florence et al, , 2011 have also been developed, showing that it is possible to switch SUR preference with chemical modifications to the scaffold. To our knowledge, the only unique pancreatic K ATP channel activator chemotypes reported in the last 2 decades were identified in screens of small-molecule libraries.…”

Section: Discussionmentioning

confidence: 99%

Direct Activation ofβ-Cell K_ATPChannels with a Novel Xanthine Derivative

et al. 2014

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ATP-regulated potassium (K ATP ) channel complexes of inward rectifier potassium channel (K ir ) 6.2 and sulfonylurea receptor (SUR) 1 critically regulate pancreatic islet b-cell membrane potential, calcium influx, and insulin secretion, and consequently, represent important drug targets for metabolic disorders of glucose homeostasis. The K ATP channel opener diazoxide is used clinically to treat intractable hypoglycemia caused by excessive insulin secretion, but its use is limited by off-target effects due to lack of potency and selectivity. Some progress has been made in developing improved K ir 6.2/SUR1 agonists from existing chemical scaffolds and compound screening, but there are surprisingly few distinct chemotypes that are specific for SUR1-containing K ATP channels. Here we report the serendipitous discovery in a highthroughput screen of a novel activator of K ir 6.2/SUR1: VU0071063The xanthine derivative rapidly and dose-dependently activates K ir 6.2/SUR1 with a half-effective concentration (EC 50 ) of approximately 7 mM, is more efficacious than diazoxide at low micromolar concentrations, directly activates the channel in excised membrane patches, and is selective for SUR1-over SUR2A-containing K ir 6.1 or K ir 6.2 channels, as well as K ir 2.1, K ir 2.2, K ir 2.3, K ir 3.1/3.2, and voltage-gated potassium channel 2.1. Finally, we show that VU0071063 activates native K ir 6.2/SUR1 channels, thereby inhibiting glucose-stimulated calcium entry in isolated mouse pancreatic b cells. VU0071063 represents a novel tool/compound for investigating b-cell physiology, K ATP channel gating, and a new chemical scaffold for developing improved activators with medicinal chemistry.

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Section: Discussionmentioning

confidence: 99%

Direct Activation ofβ-Cell K_ATPChannels with a Novel Xanthine Derivative

et al. 2014

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“…21 In previous works, we described novel series of cromakalim analogues as potential K ATP channel openers belonging to 2,2-dimethylchromans. [22][23][24][25][26][27][28][29][30] The introduction of a phenylurea or a phenylthiourea residue at the 4-position of the chroman ring led to compounds such as 6 and 7 ( Fig. 1), which, in contrast to cromakalim, were found to exert a strong opening activity on the pancreatic SUR1-type K ATP channels.…”

Section: Introductionmentioning

confidence: 99%

2,2-Dimethyl-3,4-dihydro-2H-1,4-benzoxazines as isosteres of 2,2-dimethylchromans acting as inhibitors of insulin release and vascular smooth muscle relaxants

et al. 2019

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“…Figure 1. [18][19][20][21][22][23][24][25][26] Figure1 illustrates examples of typical 2,2-dimethylchromans developed by our research group. secretory process may also be observed with drugs targeting the L-type voltage-operated calcium channels.…”

Section: Introductionmentioning

confidence: 99%

“…[17] Within this context, we previously described an ovel series of cromakalim analogues. [18][19][20][21][22][23][24][25][26] Figure1 illustrates examples of typical 2,2-dimethylchromans developed by our research group. Most of the compounds were characterizedb yt he presenceo fa ne lectronegative substituent at the 6-position of the chroman nucleus( halogen atom, sulfonamide group, carbamate group) and by the presence, at the 4-position, of an amide functionoraurea/thiourea functionasapossible isosteric substitute.…”

Section: Introductionmentioning

confidence: 99%

Deciphering Structure–Activity Relationships in a Series of 2,2‐Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants

et al. 2017

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4,6-Disubstituted 2,2-dimethylchromans are reported as pharmacologically active compounds that mainly target the ATP-sensitive potassium channels. The present study is an attempt to characterize the impact of the nature of substituents introduced at the 4- and 6-positions of 2,2-dimethylchromans on their capacities to inhibit insulin release from pancreatic β-cells or to relax vascular smooth muscle cells, both biological responses that are supposed to reflect interaction with specific ion channels. From the core structure 4-amino-2,2-dimethylchroman, a progressive increase in the steric hindrance of the chemical functionalities introduced at the 4-position (amino, formamido, acetamido, arylureido/thioureido) and at the 6-position (amino, formamido, acetamido, alkoxycarbonylamino) led to a progressive magnification of the inhibitory effect on the insulin release process and, to a lesser extent, of the vasorelaxant activity. Moreover, the dextrorotatory enantiomer of 2,2-dimethylchroman compound 29 was more potent than its levorotatory counterpart for inhibiting the insulin secretory process. Additional pharmacological investigations suggested, however, that the myorelaxant activity of 11 and 15 resulted from a direct Ca entry blockade.

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Synthesis and pharmacological evaluation of some N-arylsulfonyl-N-methyl-N′-(2,2-dimethyl-2H-1-benzopyran-4-yl)ureas structurally related to cromakalim

Cited by 10 publications

References 13 publications

Direct Activation ofβ-Cell K_ATPChannels with a Novel Xanthine Derivative

Direct Activation ofβ-Cell K_ATPChannels with a Novel Xanthine Derivative

2,2-Dimethyl-3,4-dihydro-2H-1,4-benzoxazines as isosteres of 2,2-dimethylchromans acting as inhibitors of insulin release and vascular smooth muscle relaxants

Deciphering Structure–Activity Relationships in a Series of 2,2‐Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants

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Synthesis and pharmacological evaluation of some N-arylsulfonyl-N-methyl-N′-(2,2-dimethyl-2H-1-benzopyran-4-yl)ureas structurally related to cromakalim

Cited by 10 publications

References 13 publications

Direct Activation ofβ-Cell KATPChannels with a Novel Xanthine Derivative

Direct Activation ofβ-Cell KATPChannels with a Novel Xanthine Derivative

2,2-Dimethyl-3,4-dihydro-2H-1,4-benzoxazines as isosteres of 2,2-dimethylchromans acting as inhibitors of insulin release and vascular smooth muscle relaxants

Deciphering Structure–Activity Relationships in a Series of 2,2‐Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants

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Direct Activation ofβ-Cell K_ATPChannels with a Novel Xanthine Derivative

Direct Activation ofβ-Cell K_ATPChannels with a Novel Xanthine Derivative