Synthesis and Hypoglycemic Activity of Substituted 8-(1-Piperazinyl)imidazopyrazines

Article abstract of DOI:10.1021/jm00099a012

A series of alkyl- and halo-substituted 8-(1-piperazinyl)imidazo<1,2-a>pyrazines were prepared using two approaches, the condensation of α-halocarbonyl derivatives with an aminopyrazine or the oxidation-dehydration of a <(β-hydroxyalkyl)amino>pyrazine.These imidazo<1,2-a>pyrazines were evaluated for their binding affinity to the α₁, α₂, β₁, and β₂ adrenergic receptors as well as their ability to lower blood glucose in insulin resistant hyperglycemic ob/ob mice.Modifications on 8-(1-piperazinyl)imidazo<1,2-a>pyrazine (4) reduced α₂ binding, lowered hyoglycemic potency, and showed variations in binding to the α₁, β₁, and β₂ adrenergic receptors.In addition to 4, the 2-methyl, 3-methyl, and 5-methyl 8-(1-piperazinyl)imidazo<1,2-a>pyrazines (16k, 25m, and 16f, respectively) displayed high affinity for the α₂ receptor and were potent hypoglycemic agents when compared to 2-amino-7,8-dihydro-4-(1-piperazinyl)-6H-thiopyrano<3,2-d>pyrimidine (MTP-1403, 2).Receptor binding was modified by use of a 4-methylpiperazine moiety which reduced α₁ and β₁ binding while retaining some hypoglycemic activity.The structure-activity relationship for heterocyclic alkyl and halo substitution on biological activity is discussed.