Exploration of potential prodrugs of RWJ-445167, an oxyguanidine-based dual inhibitor of thrombin and factor Xa.
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.
Maryanoff
Bruce E
BE
Vascular Research Team, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. bmaryano@prdus.jnj.com
McComsey
David F
DF
Costanzo
Michael J
MJ
Yabut
Stephen C
SC
Lu
Tianbao
T
Player
Mark R
MR
Giardino
Edward C
EC
Damiano
Bruce P
BP
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
D000925:Anticoagulants; D002219:Carbamates; D065427:Factor Xa Inhibitors; D006146:Guanidines; D007096:Imidoesters; D011355:Prodrugs; C515002:RWJ 445167; D013449:Sulfonamides; D013917:Thrombin; D019791:Guanidine