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R. Ouedraogo, B. Becker, S. Boverie, F. Somers, M.-H. Antoine, B. Pirotte, P. Lebrun, P. de Tullio
2-Alkyl-3-Alkylamino-2H-Benzo- and Pyridothiadiazine 1,1-Dioxides: From K+ATP Channel Openers to Ca++ Channel Blockers?
A series of 2-alkyl-3-alkylamino-2Hbenzo and 2-alkyl-3-alkylamino-2Hpyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides, structurally related to BPDZ 44 and BPDZ 73, two potent pancreatic Bcells K+ ATP channel openers, were synthesized and tested on rat pancreatic islets (endocrine tissue) as well as on rat aorta rings (vascular smooth muscle tissue). Alkylation of the 2-position led to double bond tautomerization and formation of compounds with a 2Hconformation. In contrast to the previously described pyridothiadiazine dioxides, such as BPDZ 44, and 7-chlorobenzothiadiazine dioxides, such as BPDZ 73, the 2-alkylsubstituted analogs were found to be poorly active on the insulin releasing process although most drugs exhibited a vasorelaxant activity. As a result, the new 2-alkylsubstituted pyridinic compounds expressed a selectivity profile (vascular smooth muscle tissue vs pancreatic tissue) opposite to that of their nonalkylsubstituted counterparts, i.e. BPDZ 44. Additional investigations revealed that, in contrast to their non 2-alkylsubstituted analogs, the most interesting 2-methylsubstituted derivatives did not express the pharmacological profile of classical K+ATP channel openers. The pharmacological results rather suggest that alkylation of the 2-position of the thiadiazine ring led to drugs that could act as Ca2+ channel blockers rather than as potassium channel openers.
Biological Chemistry, Walter de Gruyter
Print ISSN: 1431-6730
Volume: 383, 11/2002
Pages: 1759 - 1768