Synthesis and pharmacokinetic and pharmacodynamic evaluation of the forodesine HCl analog BCX-3040.
Forodesine HCl is a potent inhibitor of the enzyme purine nucleoside phosphorylase (PNP) and is currently in clinical trials for the treatment of leukemia and lymphoma. Animal models indicated that forodesine HCl would have low oral bioavailability in humans and it was initially developed as an intravenous formulation. We were interested in identifying analogs of forodesine HCl with improved oral bioavailability. The 2'-deoxy analog (BCX-3040) was synthesized and its pharmacokinetic and pharmacodynamic properties compared with forodesine HCl.
Kezar
Hollis S
HS
BioCryst Pharmaceuticals Inc., Birmingham, Alabama 35244, USA.
Kilpatrick
J Michael
JM
Phillips
Deborah
D
Kellogg
Debbie
D
Zhang
Jianwen
J
Morris
Philip E
PE
D000284:Administration, Oral; D000818:Animals; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006595:Hexosamines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology; D008223:Lymphoma / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D006595:Hexosamines; C012325:forosamine; D011683:Purine-Nucleoside Phosphorylase