Article (Scientific journals)
Modulation of the 6-position of benzopyran derivatives and inhibitory effects on the insulin releasing process
Florence, Xavier; Dilly, Sébastien; De Tullio, Pascal et al.
2011In Bioorganic and Medicinal Chemistry
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Keywords :
Benzopyran derivatives; ATP-sensitive potassium channels; Potassium Channel Openers; Cromakalim analogues; Insulin secretion; Smooth muscle contractile activity
Abstract :
[en] The synthesis of different series of 4- and 6-substituted R/S-3,4-dihydro-2,2-dimethyl-2H-1- benzopyrans is described. All of these new benzopyran derivatives were bearing, at the 4- position, a phenylthiourea moiety substituted on the phenyl ring by a meta or a para-electronwithdrawing group such as Cl or CN. The study aimed at exploring the influence of the nature of the substituent at the 6-position in order to develop new benzopyran-type KATP channel activators exhibiting an improved selectivity towards the insulin secreting cells. The original compounds were examined in vitro on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (vasorelaxant effect) and their activity was compared to that of the reference KATP channel activators (±)-cromakalim, (±)-pinacidil, diazoxide and to previously synthesized cromakalim analogues. Structure–activity relationships indicated that the inhibitory effect on the insulin secreting cells was related to the lipophilicity of the molecules and to the size of the substituent located at the 6-position. A marked inhibitory activity on the insulin secretory process was obtained with molecules bearing a bulky tertbutyloxycarbonylamino group at the 6-position (20-23). The latter compounds were found to have the same efficacy on the pancreatic endocrine tissue than some previously described molecules. Lastly, radioisotopic experiments further identified R/S-N-4-chlorophenyl-N’-(6- tert-butyloxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)thiourea (23) as a KATP channel opener.
Research center :
Laboratoire de Chimie Pharmaceutique, CIRM, Université de Liège
Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles
Disciplines :
Pharmacy, pharmacology & toxicology
Computer science
Author, co-author :
Florence, Xavier;  Université Libre de Bruxelles - ULB > Laboratoire de Pharmacodynamie et de Thérapeutique
Dilly, Sébastien ;  Université de Liège - ULiège > CIRM > Laboratoire de Chimie Pharmaceutique
De Tullio, Pascal ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Pirotte, Bernard ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Lebrun, Philippe;  Université Libre de Bruxelles - ULB > Laboratoire de Pharmacodynamie et de Thérapeutique
Language :
English
Title :
Modulation of the 6-position of benzopyran derivatives and inhibitory effects on the insulin releasing process
Publication date :
2011
Journal title :
Bioorganic and Medicinal Chemistry
ISSN :
0968-0896
eISSN :
1464-3391
Publisher :
Elsevier Science, Oxford, United Kingdom
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
FRIA - Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture [BE]
The National Fund for Scientific Research (F.N.R.S., Belgium)
Available on ORBi :
since 09 June 2011

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