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Zhang X, Jiang W, Jacutin-Porte S, et al. Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors. ACS Med Chem Lett. 2013;5(2):188-92doi: 10.1021/ml400453z.
Zhang, X., Jiang, W., Jacutin-Porte, S., Glunz, P. W., Zou, Y., Cheng, X., Nirschl, A. H., Wurtz, N. R., Luettgen, J. M., Rendina, A. R., Luo, G., Harper, T. M., Wei, A., Anumula, R., Cheney, D. L., Knabb, R. M., Wong, P. C., Wexler, R. R., & Priestley, E. S. (2014). Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors. ACS medicinal chemistry letters, 5(2), 188-92. https://doi.org/10.1021/ml400453z
Zhang, Xiaojun, et al. "Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors." ACS medicinal chemistry letters vol. 5,2 (2014): 188-92. doi: https://doi.org/10.1021/ml400453z
Zhang X, Jiang W, Jacutin-Porte S, Glunz PW, Zou Y, Cheng X, Nirschl AH, Wurtz NR, Luettgen JM, Rendina AR, Luo G, Harper TM, Wei A, Anumula R, Cheney DL, Knabb RM, Wong PC, Wexler RR, Priestley ES. Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors. ACS Med Chem Lett. 2013 Dec 26;5(2):188-92. doi: 10.1021/ml400453z. eCollection 2014 Feb 13. PMID: 24900796; PMCID: PMC4027585.
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ACS Med Chem Lett. 2013 Dec 26;5(2):188-92. doi: 10.1021/ml400453z. eCollection 2014 Feb 13.

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

ACS medicinal chemistry letters

Xiaojun Zhang, Wen Jiang, Swanee Jacutin-Porte, Peter W Glunz, Yan Zou, Xuhong Cheng, Alexandra H Nirschl, Nicholas R Wurtz, Joseph M Luettgen, Alan R Rendina, Gang Luo, Timothy M Harper, Anzhi Wei, Rushith Anumula, Daniel L Cheney, Robert M Knabb, Pancras C Wong, Ruth R Wexler, E Scott Priestley

Affiliations

  1. Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
  2. Bristol-Myers Squibb R&D , US Route 206 & Province Line Road, Princeton, New Jersey 08543-4000, United States.
  3. Biocon BMS R&D Center (BBRC), Syngene International Ltd. , Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India.

PMID: 24900796 PMCID: PMC4027585 DOI: 10.1021/ml400453z

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.

Keywords: TF-FVIIa inhibitor; aminoisoquinoline; anticoagulant; phenylglycinamide; phenylpyrrolidine; structure-based drug design

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