title: Discovery of 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor.
abstract: Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).
authors.affiliation: Discovery Chemistry, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. mimi.quan@bms.com
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
authors.forename: Qi
authors.initials: Q
authors.lastname: Han
authors.forename: Donald J P
authors.initials: DJ
authors.lastname: Pinto
authors.forename: Ming Y
authors.initials: MY
authors.lastname: He
authors.forename: Renhua
authors.initials: R
authors.lastname: Li
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ellis
authors.forename: Charles G
authors.initials: CG
authors.lastname: Clark
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Teleha
authors.forename: Jung-Hui
authors.initials: JH
authors.lastname: Sun
authors.forename: Richard S
authors.initials: RS
authors.lastname: Alexander
authors.forename: Steve
authors.initials: S
authors.lastname: Bai
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D004285:Dogs; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010539:Permeability; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000517:prevention & control
chemical_list: D001798:Blood Proteins; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007093:Imidazoles; D007555:Isoxazoles; D011720:Pyrazoles; C500057:razaxaban