Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Part 4: Biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries

Dana Ferraris, Rica Pargas Ficco, David Dain, Mark Ginski, Susan Lautar, Kathy Lee-Wisdom, Shi Liang, Qian Lin, May X C Lu, Lisa Morgan, Bert Thomas, Lawrence R. Williams, Jie Zhang, Yinong Zhou, Vincent J. Kalish

Research output: Contribution to journalArticle

Abstract

A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC50=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.

Original languageEnglish (US)
Pages (from-to)3695-3707
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number17
DOIs
StatePublished - Aug 15 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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  • Cite this

    Ferraris, D., Ficco, R. P., Dain, D., Ginski, M., Lautar, S., Lee-Wisdom, K., Liang, S., Lin, Q., Lu, M. X. C., Morgan, L., Thomas, B., Williams, L. R., Zhang, J., Zhou, Y., & Kalish, V. J. (2003). Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Part 4: Biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries. Bioorganic and Medicinal Chemistry, 11(17), 3695-3707. https://doi.org/10.1016/S0968-0896(03)00333-X