title: Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors.
abstract: Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of distribution, and a short t 1/2 in dog PK studies.
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Swanee
authors.initials: S
authors.lastname: Jacutin-Porte
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Glunz
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Nirschl
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Wurtz
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Harper
authors.affiliation: Bristol-Myers Squibb R&D , US Route 206 & Province Line Road, Princeton, New Jersey 08543-4000, United States.
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.affiliation: Biocon BMS R&D Center (BBRC), Syngene International Ltd. , Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India.
authors.forename: Rushith
authors.initials: R
authors.lastname: Anumula
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.affiliation: Bristol-Myers Squibb R&D , US Route 206 & Province Line Road, Princeton, New Jersey 08543-4000, United States.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
keywords: TF-FVIIa inhibitor; aminoisoquinoline; anticoagulant; phenylglycinamide; phenylpyrrolidine; structure-based drug design