Journal of Medicinal Chemistry p. 3845 - 3857 (1992)
Update date:2022-09-26
Topics:
Meurer, Laura C.
Tolman, Richard L.
Chapin, Edward W.
Saperstein, Richard
Vicario, Pasquale P.
et al.
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.
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Doi:10.1016/0223-5234(92)90138-Q
(1992)Doi:10.1055/s-1999-3612
(1999)Doi:10.1021/jm00054a003
(1993)Doi:10.3390/molecules18032683
(2013)Doi:10.1039/c3cc42238k
(2013)Doi:10.1039/c39920001039
(1992)