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Bembenek SD, Venkatesan H, Peltier HM, et al. Beyond Traditional Structure-Based Drug Design: The Role of Iron Complexation, Strain, and Water in the Binding of Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylase 2. ACS Omega. 2019;4(4):6703-6708doi: 10.1021/acsomega.9b00199.
Bembenek, S. D., Venkatesan, H., Peltier, H. M., Rosen, M. D., Barrett, T. D., Kanelakis, K. C., Palomino, H. L., Brondstetter, T. I., Mirzadegan, T., & Rabinowitz, M. H. (2019). Beyond Traditional Structure-Based Drug Design: The Role of Iron Complexation, Strain, and Water in the Binding of Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylase 2. ACS omega, 4(4), 6703-6708. https://doi.org/10.1021/acsomega.9b00199
Bembenek, Scott D, et al. "Beyond Traditional Structure-Based Drug Design: The Role of Iron Complexation, Strain, and Water in the Binding of Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylase 2." ACS omega vol. 4,4 (2019): 6703-6708. doi: https://doi.org/10.1021/acsomega.9b00199
Bembenek SD, Venkatesan H, Peltier HM, Rosen MD, Barrett TD, Kanelakis KC, Palomino HL, Brondstetter TI, Mirzadegan T, Rabinowitz MH. Beyond Traditional Structure-Based Drug Design: The Role of Iron Complexation, Strain, and Water in the Binding of Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylase 2. ACS Omega. 2019 Apr 30;4(4):6703-6708. doi: 10.1021/acsomega.9b00199. Epub 2019 Apr 12. PMID: 31179408; PMCID: PMC6547624.
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ACS Omega. 2019 Apr 30;4(4):6703-6708. doi: 10.1021/acsomega.9b00199. Epub 2019 Apr 12.

Beyond Traditional Structure-Based Drug Design: The Role of Iron Complexation, Strain, and Water in the Binding of Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylase 2.

ACS omega

Scott D Bembenek, Hariharan Venkatesan, Hillary M Peltier, Mark D Rosen, Terrance D Barrett, Kimon C Kanelakis, Heather L Palomino, Theresa I Brondstetter, Taraneh Mirzadegan, Michael H Rabinowitz

Affiliations

  1. Discovery Sciences and Cardiovascular Metabolic Therapeutic Area, Janssen Research & Development, San Diego, California 92121, United States.
  2. Janssen Research & Development, San Diego, California 92121, United States.

PMID: 31179408 PMCID: PMC6547624 DOI: 10.1021/acsomega.9b00199

Abstract

A combination of structure-based drug design and medicinal chemistry efforts led us from benzimidazole-2-carboxamide with modestly active hypoxia-inducible factor prolyl hydroxylase 2 inhibition to certain benzimidazole-2-pyrazole carboxylic acids that were more potent as well as orally efficacious stimulators of erythropoietin secretion in our in vivo mouse model. To better understand the structure-activity relationship, it was necessary to account for (i) the complexation of the ligand with the active site Fe

Conflict of interest statement

The authors declare no competing financial interest.

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