Sebille S, Gall D, de Tullio P, Florence X, Lebrun P, Pirotte B
Design, synthesis, and pharmacological evaluation of R/S-3,4-dihydro-2,2-dimethyl- 6-halo-4-(phenylaminocarbonylamino)-2H-1-benzopyrans: toward tissue-selective pancreatic beta-cell KATP channel openers structurally related to (+/-)-cromakalim. [In Vitro, Journal Article, Research Support, Non-U.S. Gov't]
J Med Chem 2006 Jul 27; 49(15):4690-7.
In the search of a novel series of benzopyrans structurally related to (+/-)-cromakalim and acting as pancreatic beta-cell potassium channel openers, several R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminocarbonylamino)-2H-1-benzopyrans with or without a substituent on the phenyl ring in the 4-position were synthesized. Their activity on rat-insulin-secreting cells and rat aorta rings was compared to that of the K(ATP) channel activators (+/-)-cromakalim, diazoxide, (+/-)-pinacidil, and compound 4. Structure-activity relationships indicated that the most pronounced inhibitory activity on the pancreatic tissue was obtained by introducing a meta- or para-electron-withdrawing group (a chlorine atom) on the C-4 phenyl ring (drugs 37-42). Such molecules, unlike the parent compound (+/-)-cromakalim, also exhibited a high selectivity for the pancreatic tissue versus the vascular tissue. Radioisotopic and electrophysiological investigations performed with R/S-6-chloro-4-(3-chlorophenylaminocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (38) confirmed that the drug activated pancreatic KATP channels.
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