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New R/S-3,4-dihydro-2,2-dimethyl-2H-1-benzopyrans as K(ATP) channel openers: modulation of the 4-position.

Authors :
Florence X
Sebille S
Tullio Pd
Lebrun P
Pirotte B
Source :
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2009 Nov 15; Vol. 17 (22), pp. 7723-31. Date of Electronic Publication: 2009 Sep 25.
Publication Year :
2009

Abstract

The present work aimed at exploring a series of diversely 4-arylthiourea-substituted R/S-3,4-dihydro-2,2-dimethyl-6-halo-2H-1-benzopyrans structurally related to (+/-)-cromakalim. These new compounds were examined in vitro as putative potassium channel openers (PCOs) on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (relaxation of aorta ring) and their activity was compared to that of the reference K(ATP) channel activators (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and of previously reported cromakalim analogues. Structure-activity relationships indicated that the most pronounced inhibitory activity on the insulin secretory process was obtained with molecules bearing a strong meta- or para-electron-withdrawing group (CN or NO(2)) on the phenyl ring of the arylthiourea moiety at the 4-position of the benzopyran nucleus (compounds 12-23). Among those, R/S-6-chloro-4-(4-cyanophenylaminothiocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (16) was found to be the most potent benzopyran-type inhibitor of insulin release ever described. Most of these original benzopyran derivatives show increased selectivity for pancreatic versus vascular tissue. Radioisotopic investigations indicated that these new compounds activated pancreatic K(ATP) channels.

Details

Language :
English
ISSN :
1464-3391
Volume :
17
Issue :
22
Database :
MEDLINE
Journal :
Bioorganic & medicinal chemistry
Publication Type :
Academic Journal
Accession number :
19822435
Full Text :
https://doi.org/10.1016/j.bmc.2009.09.041