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Structural Chemistry and Molecular Modeling in the Design of DPP4 Inhibitors

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Multifaceted Roles of Crystallography in Modern Drug Discovery

Abstract

Inhibition of dipeptidyl peptidase IV (DPP-4) is an established approach for the treatment of type 2 diabetes. In 2006, Sitagliptin phosphate, a potent, orally bioavailable and highly selective small molecule DPP-4 inhibitor was approved by the FDA as once daily novel drug for the treatment of type 2 diabetes. Given the clinical success of sitagliptin our laboratories have been interested in generating analogues amenable for once-weekly dosing, to increase medication adherence. The first of such compounds was approved for preclinical and clinical development in 2008. During the back-up development stages, structural chemistry was used to generate new ideas, as well as evaluate in-silico proposals and screening results, and used to guide and significantly accelerate the drug discovery process.

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Acknowledgments

The author would like to thanks all the teams that worked on the DPP4 inhibitor programs over the years, especially the chemistry and biology leaders, Ann E Weber and Nancy A. Thornberry. Special thanks to Hubert Josien, Dmitri Pissarnitski and Wen Lian Wu, whose molecules are discussed in the paper. Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357.

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Authors and Affiliations

  1. Structural Chemistry Department, Merck & Co., Inc, Kenilworth, NJ, 07033, USA

    Giovanna Scapin

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  1. Giovanna Scapin
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Correspondence to Giovanna Scapin .

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Editors and Affiliations

  1. Structural Chemistry Department, Merck & Co, Inc., Kenilworth, New Jersey, USA

    Giovanna Scapin

  2. Center for Advanced Biotechnology and Medicine, and Rutgers University, Piscataway, New Jersey, USA

    Disha Patel

  3. Center for Advanced Biotechnology and Medicine, and Rutgers University, Piscataway, New Jersey, USA

    Eddy Arnold

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Scapin, G. (2015). Structural Chemistry and Molecular Modeling in the Design of DPP4 Inhibitors. In: Scapin, G., Patel, D., Arnold, E. (eds) Multifaceted Roles of Crystallography in Modern Drug Discovery. NATO Science for Peace and Security Series A: Chemistry and Biology. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9719-1_5

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