Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor

Edited by Keith R. Yamamoto, University of California, San Francisco, CA, and approved September 3, 2009
October 27, 2009
106 (43) 18114-18119

Abstract

Crystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain–agonist complex of the D-prolinamide derivative 11. The utility of the channel was further exemplified through the design of a potent phenylindazole in which structural motifs, seen to interact with the traditional GR ligand pocket, were abandoned and replaced by interactions within the new channel. Occupation of the channel was confirmed with a second GR crystal structure of this truncated D-alaninamide derivative 13. Compound 11 displays properties compatible with development as an intranasal solution formulation, whereas oral bioavailability has been demonstrated with a related truncated exemplar 14. Data with the pyrrolidinone amide 12 demonstrate the potential for further elaboration within the “meta” channel to deliver compounds with selectivity for the desired transrepressive activity of glucocorticoids. The discovery of these interactions with this important receptor offers significant opportunities for the design of novel GR modulators.

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Data Availability

Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3K22 and 3K23).

Acknowledgments.

We thank the following for their valuable contributions to this work: David Brown, Matilde Caivano, Margaret Clackers, Anette Miles-Williams, and Rosemary Sasse (screening and compound profiling); Bhavesh Patel, Heather Barnett, Karl Collins, and Natalie Wellaway (chemistry); James Gray, David Lugo, and Cesar Ramirez-Molina (drug metabolism); Eugene Stewart (computational chemistry); and Eric Hortense and Steve Jackson (analytical chemistry).

Supporting Information

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References

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Information & Authors

Information

Published in

The cover image for PNAS Vol.106; No.43
Proceedings of the National Academy of Sciences
Vol. 106 | No. 43
October 27, 2009
PubMed: 19822747

Classifications

Data Availability

Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3K22 and 3K23).

Submission history

Received: August 13, 2009
Published online: October 27, 2009
Published in issue: October 27, 2009

Keywords

  1. drug design
  2. AlleGrow
  3. glucocorticoid modulation
  4. intranasal glucocorticoid

Acknowledgments

We thank the following for their valuable contributions to this work: David Brown, Matilde Caivano, Margaret Clackers, Anette Miles-Williams, and Rosemary Sasse (screening and compound profiling); Bhavesh Patel, Heather Barnett, Karl Collins, and Natalie Wellaway (chemistry); James Gray, David Lugo, and Cesar Ramirez-Molina (drug metabolism); Eugene Stewart (computational chemistry); and Eric Hortense and Steve Jackson (analytical chemistry).

Notes

This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0909125106/DCSupplemental.

Authors

Affiliations

Keith Biggadike1 [email protected]
Medicinal Chemistry, Respiratory Center of Excellence for Drug Discovery (CEDD), GlaxoSmithKline Medicines Research Center, Stevenage, Hertfordshire SG1 2NY, United Kingdom;
Randy K. Bledsoe
Biologicals Reagents and Assay Development;
Diane M. Coe
Medicinal Chemistry, Respiratory Center of Excellence for Drug Discovery (CEDD), GlaxoSmithKline Medicines Research Center, Stevenage, Hertfordshire SG1 2NY, United Kingdom;
Tony W. J. Cooper
Medicinal Chemistry, Respiratory Center of Excellence for Drug Discovery (CEDD), GlaxoSmithKline Medicines Research Center, Stevenage, Hertfordshire SG1 2NY, United Kingdom;
David House
Medicinal Chemistry, Respiratory Center of Excellence for Drug Discovery (CEDD), GlaxoSmithKline Medicines Research Center, Stevenage, Hertfordshire SG1 2NY, United Kingdom;
Marie A. Iannone
Biochemical and Cellular Targets;
Simon J. F. Macdonald
Medicinal Chemistry, Respiratory Center of Excellence for Drug Discovery (CEDD), GlaxoSmithKline Medicines Research Center, Stevenage, Hertfordshire SG1 2NY, United Kingdom;
Kevin P. Madauss
Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline Medicines Research Center, Research Triangle Park, NC 27709;
Iain M. McLay
Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline Medicines Research Center, Stevenage, Hertfordshire SG1 2NY, United Kingdom;
Tracy J. Shipley
Medicinal Chemistry, Respiratory Center of Excellence for Drug Discovery (CEDD), GlaxoSmithKline Medicines Research Center, Stevenage, Hertfordshire SG1 2NY, United Kingdom;
Simon J. Taylor
Drug Metabolism and Pharmacokinetics, Respiratory CEDD; and
Thuy B. Tran
Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline Medicines Research Center, Research Triangle Park, NC 27709;
Iain J. Uings
Epigenetics Discovery Performance Unit, Immuno-Inflammation CEDD, GlaxoSmithKline Medicines Research Center, Stevenage, Hertfordshire SG1 2NY, United Kingdom
Victoria Weller
Medicinal Chemistry, Respiratory Center of Excellence for Drug Discovery (CEDD), GlaxoSmithKline Medicines Research Center, Stevenage, Hertfordshire SG1 2NY, United Kingdom;
Shawn P. Williams
Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline Medicines Research Center, Research Triangle Park, NC 27709;

Notes

1
To whom correspondence should be addressed. E-mail: [email protected]
Author contributions: K.B., D.M.C., T.W.J.C., D.H., S.J.F.M., K.P.M., I.M.M., and I.J.U. designed research; R.K.B., T.W.J.C., D.H., M.A.I., I.M.M., T.J.S., S.J.T., T.B.T., and V.W. performed research; K.B., R.K.B., T.W.J.C., D.H., K.P.M., I.M.M., and S.P.W. analyzed data; and K.B., K.P.M., I.M.M., and I.J.U. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor
    Proceedings of the National Academy of Sciences
    • Vol. 106
    • No. 43
    • pp. 18041-18427

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