title: Design and synthesis of factor Xa inhibitors and their prodrugs.
abstract: In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency (14, IC(50)=0.028 microM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats.
authors.affiliation: Department of Medicinal Chemistry, Millennium Pharmaceuticals, Inc., 256 East Grand Ave., South, San Francisco, CA 94080, USA. song@mpi.com
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Song
authors.forename: Lane
authors.initials: L
authors.lastname: Clizbe
authors.forename: Chhaya
authors.initials: C
authors.lastname: Bhakta
authors.forename: Willy
authors.initials: W
authors.lastname: Teng
authors.forename: Paul
authors.initials: P
authors.lastname: Wong
authors.forename: Brian
authors.initials: B
authors.lastname: Huang
authors.forename: Katherine
authors.initials: K
authors.lastname: Tran
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
authors.forename: Gary
authors.initials: G
authors.lastname: Park
authors.forename: Andrea
authors.initials: A
authors.lastname: Reed
authors.forename: Robert M
authors.initials: RM
authors.lastname: Scarborough
authors.forename: Bing Yan
authors.initials: BY
authors.lastname: Zhu
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D015195:Drug Design; D065427:Factor Xa Inhibitors; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000578:Amidines; D065427:Factor Xa Inhibitors; D011355:Prodrugs; D015842:Serine Proteinase Inhibitors