title: Poly(ethylene glycol) prodrugs of the CDK inhibitor, alsterpaullone (NSC 705701): synthesis and pharmacokinetic studies.
abstract: Two methods were devised to conjugate PEG to alsterpaullone (NSC 705701) via the N of the indole ring portion of the molecule. In the first approach, activation of the indole was accomplished by reaction with p-nitrophenyl chloroformate to produce a reactive carbamate that was then condensed with a mono blocked diamine to form a urea bond followed by deblocking and conjugation to PEG. The second route used the anion of the indole and produced a carbamate bond. Both compounds were highly water soluble, were stable in buffer, and released alsterpaullone in vitro and in vivo. Studies were conducted in mice to investigate the influence of PEGylation on the plasma pharmacokinetics of alsterpaullone. The total plasma clearance rate was decreased up to 32-fold, and the biological halflife lengthened up to 8-fold when alsterpaullone was injected i.v. as a PEG-conjugate and compared to injection of the unconjugated compound. The most pronounced effect on the pharmacokinetics of alsterpaullone was produced by a 40-kDa PEG urea-linked conjugate. When the 40- and 20-kDa urea-linked conjugates were administered by i.p. injection, high relative bioavailability (46% and 99%, respectively) of alsterpaullone was observed.
authors.affiliation: Enzon Pharmaceuticals Inc., Research & Development Division, 20 Kingsbridge Road, Piscataway, New Jersey 08854, USA. richard.greenwald@enzon.com
authors.forename: Richard B
authors.initials: RB
authors.lastname: Greenwald
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Xia
authors.forename: Dechun
authors.initials: D
authors.lastname: Wu
authors.forename: Stephen
authors.initials: S
authors.lastname: Nervi
authors.forename: Sherman F
authors.initials: SF
authors.lastname: Stinson
authors.forename: Eva
authors.initials: E
authors.lastname: Majerova
authors.forename: Chris
authors.initials: C
authors.lastname: Bramhall
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Zaharevitz
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*
chemical_list: D001552:Benzazepines; D007211:Indoles; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; C120793:alsterpaullone; D011092:Polyethylene Glycols; D018844:Cyclin-Dependent Kinases