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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.

SUBMITTER: Zhang X

PROVIDER: S-EPMC4027585 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors.

Zhang Xiaojun X Jiang Wen W Jacutin-Porte Swanee S Glunz Peter W PW Zou Yan Y Cheng Xuhong X Nirschl Alexandra H AH Wurtz Nicholas R NR Luettgen Joseph M JM Rendina Alan R AR Luo Gang G Harper Timothy M TM Wei Anzhi A Anumula Rushith R Cheney Daniel L DL Knabb Robert M RM Wong Pancras C PC Wexler Ruth R RR Priestley E Scott ES

ACS medicinal chemistry letters 20131226 2

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 ...[more]

PMID: 24900796

Dataset Information

Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors.

Publications

Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors.

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