- Synthesis and Hypoglycemic Activity of Substituted 8-(1-Piperazinyl)imidazopyrazines
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A series of alkyl- and halo-substituted 8-(1-piperazinyl)imidazopyrazines were prepared using two approaches, the condensation of α-halocarbonyl derivatives with an aminopyrazine or the oxidation-dehydration of a pyrazine.These imidazopyrazines 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)imidazopyrazine (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)imidazopyrazines (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-thiopyranopyrimidine (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.
- Meurer, Laura C.,Tolman, Richard L.,Chapin, Edward W.,Saperstein, Richard,Vicario, Pasquale P.,et al.
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p. 3845 - 3857
(2007/10/02)
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