title: 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.
authors.affiliation: Carbohydrate Chemistry Team, Industrial Research Limited, P.O. Box 31310, Lower Hutt 5040, New Zealand.
authors.forename: Keith
authors.initials: K
authors.lastname: Clinch
authors.forename: Gary B
authors.initials: GB
authors.lastname: Evans
authors.forename: Richard F G
authors.initials: RF
authors.lastname: Fröhlich
authors.forename: Richard H
authors.initials: RH
authors.lastname: Furneaux
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kelly
authors.forename: Laurent
authors.initials: L
authors.lastname: Legentil
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Murkin
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
authors.forename: Peter C
authors.initials: PC
authors.lastname: Tyler
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Woolhouse
mesh_terms: 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
chemical_list: D011759:Pyrrolidines; D011683:Purine-Nucleoside Phosphorylase; D000225:Adenine; D000241:Adenosine; C517546:galidesivir