Novel synthesis of the hexahydroimidazo[1,5b]isoquinoline scaffold: Application to the synthesis of glucocorticoid receptor modulators

Hai Yun Xiao, Dauh Rurng Wu, Mary F. Malley, Jack Z. Gougoutas, Sium F. Habte, Mark D. Cunningham, John E. Somerville, John H. Dodd, Joel C. Barrish, Steven G. Nadler, T. G.Murali Dhar

Research output: Contribution to journalArticle

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Abstract

The first stereoselective synthesis of the hexahydroimidazo[1,5b] isoquinoline (HHII) scaffold as a surrogate for the steroidal A-B ring system is described. The structure-activity relationships of the analogs derived from this scaffold show that the basic imidazole moiety is tolerated by the glucocorticoid receptor (GR) in terms of binding affinity, although the partial agonist activity in the transrepressive assays depends on the substitution pattern on the B-ring.More importantly, most compounds in the HHII series bearing a tertiary alcohol moiety on the B-ring are either inactive or significantly less active in inducing GR-mediated transactivation, thus displaying a "dissociated" pharmacology in vitro.

Original languageEnglish (US)
Pages (from-to)1270-1280
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number3
DOIs
StatePublished - Mar 1 2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Xiao, H. Y., Wu, D. R., Malley, M. F., Gougoutas, J. Z., Habte, S. F., Cunningham, M. D., Somerville, J. E., Dodd, J. H., Barrish, J. C., Nadler, S. G., & Dhar, T. G. M. (2010). Novel synthesis of the hexahydroimidazo[1,5b]isoquinoline scaffold: Application to the synthesis of glucocorticoid receptor modulators. Journal of Medicinal Chemistry, 53(3), 1270-1280. https://doi.org/10.1021/jm901551w