Reference : Modulation of the 6-position of benzopyran derivatives and inhibitory effects on the ins...
Scientific journals : Article
Engineering, computing & technology : Computer science
Human health sciences : Pharmacy, pharmacology & toxicology
http://hdl.handle.net/2268/92672
Modulation of the 6-position of benzopyran derivatives and inhibitory effects on the insulin releasing process
English
Florence, Xavier mailto [Université Libre de Bruxelles - ULB > Laboratoire de Pharmacodynamie et de Thérapeutique > > >]
Dilly, Sébastien mailto [Université de Liège - ULg > CIRM > Laboratoire de Chimie Pharmaceutique > >]
De Tullio, Pascal mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
Pirotte, Bernard mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
Lebrun, Philippe [Université Libre de Bruxelles - ULB > Laboratoire de Pharmacodynamie et de Thérapeutique > > >]
2011
Bioorganic & Medicinal Chemistry
Elsevier Science
Yes (verified by ORBi)
International
0968-0896
1464-3391
Oxford
United Kingdom
[en] Benzopyran derivatives ; ATP-sensitive potassium channels ; Potassium Channel Openers ; Cromakalim analogues ; Insulin secretion ; Smooth muscle contractile activity
[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.
Laboratoire de Chimie Pharmaceutique, CIRM, Université de Liège ; Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles
The Formation to Research in Industry and Agriculture (F.R.I.A., Belgium) ; The National Fund for Scientific Research (F.N.R.S., Belgium)
Researchers ; Professionals ; Students
http://hdl.handle.net/2268/92672
10.1016/j.bmc.2011.05.040

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