Synthesis and hypoglycemic activity of substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines.

Abstract

A series of alkyl- and halo-substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines were prepared using two approaches, the condensation of alpha-halocarbonyl derivatives with an aminopyrazine or the oxidation-dehydration of a [(beta-hydroxyalkyl)amino]pyrazine. These imidazo[1,2-a]pyrazines were evaluated for their binding affinity to the alpha 1, alpha 2, beta 1, and beta 2 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 alpha 2 binding, lowered hypoglycemic potency, and showed variations in binding to the alpha 1, beta 1, and beta 2 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 alpha 2 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 alpha 1 and beta 1 binding while retaining some hypoglycemic activity. The structure-activity relationship for heterocyclic alkyl and halo substitution on biological activity is discussed.

• Authors: L C Meurer, R L Tolman, E W Chapin, R Saperstein, P P Vicario, M M Zrada, M MacCoss
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 35 Issue 21 Pg. 3845-57 (Oct 16 1992) ISSN: 0022-2623 [Print] United States
• PMID: 1359141 (Publication Type: Journal Article)

Chemical References

• Adrenergic alpha-Antagonists
• Hypoglycemic Agents
• Piperazines
• Pyrazines
• Receptors, Adrenergic, alpha
• Receptors, Adrenergic, beta
• 8-(1-piperazinyl)imidazo(1,2-a)pyrazine

Topics

• Adrenergic alpha-Antagonists (chemical synthesis, pharmacology)
• Animals
• Guinea Pigs
• Hypoglycemic Agents (chemical synthesis, pharmacology, therapeutic use)
• In Vitro Techniques
• Male
• Mice
• Mice, Inbred C57BL
• Piperazines (chemical synthesis, pharmacology)
• Pyrazines (chemical synthesis, pharmacology)
• Receptors, Adrenergic, alpha (drug effects)
• Receptors, Adrenergic, beta (drug effects)
• Structure-Activity Relationship