Unknown

Dataset Information

0

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

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.

SUBMITTER: Clinch K 

PROVIDER: S-EPMC2698043 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

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

Clinch Keith K   Evans Gary B GB   Fröhlich Richard F G RF   Furneaux Richard H RH   Kelly Peter M PM   Legentil Laurent L   Murkin Andrew S AS   Li Lei L   Schramm Vern L VL   Tyler Peter C PC   Woolhouse Anthony D AD  

Journal of medicinal chemistry 20090201 4

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.  ...[more]

Similar Datasets

Unknown Immucillin-H, a purine nucleoside phosphorylase transition state analog, causes non-lethal attenuation of growth in Staphylococcus aureus.
| S-EPMC3563410 | biostudies-literature
Unknown Acyclic immucillin phosphonates: second-generation inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase.
| S-EPMC3397391 | biostudies-literature
Unknown Structure of grouper iridovirus purine nucleoside phosphorylase.
| S-EPMC2815667 | biostudies-literature
Unknown Design, Synthesis, Biological Evaluation, and Crystallographic Study of Novel Purine Nucleoside Phosphorylase Inhibitors.
| S-EPMC10226123 | biostudies-literature
Unknown L-Enantiomers of transition state analogue inhibitors bound to human purine nucleoside phosphorylase.
| S-EPMC2531256 | biostudies-literature
Unknown A beta-fluoroamine inhibitor of purine nucleoside phosphorylase.
| S-EPMC4508846 | biostudies-literature
Unknown Synthesis of New 5'-Norcarbocyclic Aza/Deaza Purine Fleximers - Noncompetitive Inhibitors of <i>E.coli</i> Purine Nucleoside Phosphorylase.
| S-EPMC9114674 | biostudies-literature
Unknown Inhibition and structure of Toxoplasma gondii purine nucleoside phosphorylase.
| S-EPMC4060479 | biostudies-literature
Unknown Structure of purine nucleoside phosphorylase (DeoD) from Bacillus anthracis.
| S-EPMC1952315 | biostudies-literature
Unknown Purine nucleoside phosphorylase deficiency in two unrelated Saudi patients.
| S-EPMC2841460 | biostudies-literature