title: Exploration of potential prodrugs of RWJ-445167, an oxyguanidine-based dual inhibitor of thrombin and factor Xa.
abstract: Compound 2 (RWJ-445167; 3DP-10017), a dual inhibitor of thrombin and factor Xa, was advanced into human clinical studies. However, its oral bioavailability in humans proved to be below acceptable limits. To address this issue, we explored a prodrug approach involving numerous guanidine derivatives. Prodrug candidates of classes A (carbamate derivatives), B (imidate derivatives), and C (alkyl and acyl derivatives), compounds 3-6, were synthesized and evaluated for anticoagulant activity at 2 h after oral administration to rats. In comparison to the parent drug (2), little worthwhile improvement was observed for the prodrug candidates.
authors.affiliation: Vascular Research Team, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. bmaryano@prdus.jnj.com
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: David F
authors.initials: DF
authors.lastname: McComsey
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Costanzo
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Yabut
authors.forename: Tianbao
authors.initials: T
authors.lastname: Lu
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: Edward C
authors.initials: EC
authors.lastname: Giardino
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002219:Carbamates / Q000138:chemical synthesis; D004285:Dogs; D065427:Factor Xa Inhibitors; D019791:Guanidine / Q000031:analogs & derivatives / Q000737:chemistry; D006146:Guanidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D007096:Imidoesters / Q000138:chemical synthesis; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D000925:Anticoagulants; D002219:Carbamates; D065427:Factor Xa Inhibitors; D006146:Guanidines; D007096:Imidoesters; D011355:Prodrugs; C515002:RWJ 445167; D013449:Sulfonamides; D013917:Thrombin; D019791:Guanidine