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 β-Cell KATP Channel Openers Structurally Related to (±)-Cromakalim

• Published in: Journal of medicinal chemistry 2006-07, Vol.49 (15), p.4690-4697
• Main Authors: SEBILLE, Sophie, GALL, David, DE TULLIO, Pascal, FLORENCE, Xavier, LEBRUN, Philippe, PIROTTE, Bernard
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - physiology; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiology; Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - pharmacology; Biological and medical sciences; Cromakalim - chemistry; General and cellular metabolism. Vitamins; In Vitro Techniques; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - physiology; Ion Channel Gating - drug effects; Medical sciences; Muscle Contraction; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Patch-Clamp Techniques; Pharmacology. Drug treatments; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - chemistry; Phenylurea Compounds - pharmacology; Potassium Channels - drug effects; Rats; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060161z

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.