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

Article Details

Citation

Clinch K, Evans GB, Frohlich RF, Furneaux RH, Kelly PM, Legentil L, Murkin AS, Li L, Schramm VL, Tyler PC, Woolhouse AD

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

J Med Chem. 2009 Feb 26;52(4):1126-43. doi: 10.1021/jm801421q.

PubMed ID
19170524 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ForodesinePurine nucleoside phosphorylaseKi (nM)0.056N/AN/ADetails
Immucillin-GPurine nucleoside phosphorylaseKi (nM)0.042N/AN/ADetails