Third-generation immucillins: syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase.
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.
Clinch
Keith
K
Carbohydrate Chemistry Team, Industrial Research Limited, P.O. Box 31310, Lower Hutt 5040, New Zealand.
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
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives; D020134:Catalytic Domain; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D018583:Pliability; D011485:Protein Binding; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011759:Pyrrolidines; D011683:Purine-Nucleoside Phosphorylase; D000225:Adenine; D000241:Adenosine; C517546:galidesivir