Synthesis and Hypoglycemic Activity of Substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines

J Med Chem. 1992 Oct 16;35(21):3845-57. doi: 10.1021/jm00099a012.

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.

MeSH terms

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

Substances

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