Design, Synthesis, and Pharmacological Evaluation ofR/S-3,4-Dihydro-2,2-dimethyl- 6-halo-4-(phenylaminocarbonylamino)-2H-1-benzopyrans:  Toward Tissue-Selective Pancreatic β-CellK_ATPChannel Openers Structurally Related to (±)-Cromakalim

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-(phenylaminocarbonyl-amino)-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 KATP 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/S6-chloro-4-(3-chlorophenylaminocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (38) confirmed that the drug activated pancreatic KATP channels.