Third-generation immucillins: Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase

Keith Clinch, Gary B. Evans, Richard F G Frohlich, Richard H. Furneaux, Peter M. Kelly, Laurent Legentil, Andrew S. Murkin, Lei Li, Vern L. Schramm, Peter C. Tyler, Anthony D. Woolhouse

Research output: Contribution to journalArticle

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Abstract

ImmH (1) and DADMe-ImmH (2) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues (8-38) in order to identify simplified alternatives to 1 and 2. SerMe-ImmG (8) and DATMe- ImmG (9) displayed the lowest inhibition constants of 2.1 and 3.4 pM, respectively, vs PNP. It was postulated that the flexible natures of 8 and 9 enabled them to adopt conformations resembling those of 1 and 2 within the active site of PNP and that the positioning of two hydroxyl groups was critical for picomolar activity. SerMe-ImmH (10, K d = 5.2 pM) was shown to be orally available in mice with a long biological residence time on blood PNP.

Original languageEnglish (US)
Pages (from-to)1126-1143
Number of pages18
JournalJournal of Medicinal Chemistry
Volume52
Issue number4
DOIs
StatePublished - Feb 26 2009

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Purine-Nucleoside Phosphorylase
Purine Nucleosides
Hydroxyl Radical
Catalytic Domain
Clinical Trials
T-Lymphocytes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Clinch, K., Evans, G. B., Frohlich, R. F. G., Furneaux, R. H., Kelly, P. M., Legentil, L., ... Woolhouse, A. D. (2009). Third-generation immucillins: Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase. Journal of Medicinal Chemistry, 52(4), 1126-1143. https://doi.org/10.1021/jm801421q

Third-generation immucillins : Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase. / Clinch, Keith; Evans, Gary B.; Frohlich, Richard F G; Furneaux, Richard H.; Kelly, Peter M.; Legentil, Laurent; Murkin, Andrew S.; Li, Lei; Schramm, Vern L.; Tyler, Peter C.; Woolhouse, Anthony D.

In: Journal of Medicinal Chemistry, Vol. 52, No. 4, 26.02.2009, p. 1126-1143.

Research output: Contribution to journalArticle

Clinch, K, Evans, GB, Frohlich, RFG, Furneaux, RH, Kelly, PM, Legentil, L, Murkin, AS, Li, L, Schramm, VL, Tyler, PC & Woolhouse, AD 2009, 'Third-generation immucillins: Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase', Journal of Medicinal Chemistry, vol. 52, no. 4, pp. 1126-1143. https://doi.org/10.1021/jm801421q
Clinch, Keith ; Evans, Gary B. ; Frohlich, Richard F G ; Furneaux, Richard H. ; Kelly, Peter M. ; Legentil, Laurent ; Murkin, Andrew S. ; Li, Lei ; Schramm, Vern L. ; Tyler, Peter C. ; Woolhouse, Anthony D. / Third-generation immucillins : Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 4. pp. 1126-1143.
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