Issue 2, 2014

Identification of orally bioavailable small-molecule inhibitors of hematopoietic prostaglandin D2 synthase using X-ray fragment based drug discovery

Abstract

Using X-ray crystallographic screening, fragments 4 and 6 were identified as inhibitors of hematopoietic prostaglandin D2 synthase (H-PGDS). Both fragments induced a small protein movement in the X-ray crystal structure relative to the apo structure, where the highly polar nature of the ligand complemented the induced protein conformation. The manuscript describes the fragment optimisation of 4 and 6 followed by fragment growth to lead molecule 10. This showed favourable physicochemical properties and evidence of oral activity in blocking PGD2 generation in vivo.

Graphical abstract: Identification of orally bioavailable small-molecule inhibitors of hematopoietic prostaglandin D2 synthase using X-ray fragment based drug discovery

Article information

Article type
Concise Article
Submitted
27 Sep 2013
Accepted
04 Nov 2013
First published
21 Nov 2013

Med. Chem. Commun., 2014,5, 134-141

Identification of orally bioavailable small-molecule inhibitors of hematopoietic prostaglandin D2 synthase using X-ray fragment based drug discovery

G. Saxty, D. Norton, K. Affleck, D. Clapham, A. Cleasby, J. Coyle, P. Day, M. Frederickson, A. Hancock, H. Hobbs, J. Hutchinson, J. Le, M. Leveridge, R. McMenamin, P. Mortenson, L. Page, C. Richardson, L. Russell, E. Sherriff, S. Teague, S. Uddin and S. Hodgson, Med. Chem. Commun., 2014, 5, 134 DOI: 10.1039/C3MD00280B

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