1. Structure‐Activity Relationship and Crystallographic Studies on 4‐Hydroxypyrimidine HIF Prolyl Hydroxylase Domain Inhibitors
- Author
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Martine I. Abboud, William D. Figg, Anthony Tumber, Gareth W. Langley, Kerstin Lippl, Christopher W. Pugh, Tzu-Lan Yeh, Christopher T. Lohans, Rasheduzzaman Chowdhury, Peter J. Ratcliffe, Christopher J. Schofield, James P. Holt-Martyn, and Michael A. McDonough
- Subjects
Models, Molecular ,education ,Pyrimidinones ,Crystallography, X-Ray ,01 natural sciences ,Biochemistry ,prolyl hydroxylases ,Hypoxia-Inducible Factor-Proline Dioxygenases ,Structure-Activity Relationship ,Oxidoreductase ,hemic and lymphatic diseases ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,General Pharmacology, Toxicology and Pharmaceutics ,health care economics and organizations ,Pharmacology ,chemistry.chemical_classification ,anaemia ,Dose-Response Relationship, Drug ,Molecular Structure ,Hif prolyl hydroxylase ,010405 organic chemistry ,Chemistry ,hypoxia ,Communication ,Organic Chemistry ,structure-activity relationships ,Late stage ,Prolyl-Hydroxylase Inhibitors ,Hypoxia (medical) ,Communications ,0104 chemical sciences ,4-hydroxypyrimidine ,010404 medicinal & biomolecular chemistry ,Crystallography ,Hypoxia-inducible factors ,Prolyl Hydroxylases ,Molecular Medicine ,medicine.symptom - Abstract
The 2‐oxoglutarate‐dependent hypoxia inducible factor prolyl hydroxylases (PHDs) are targets for treatment of a variety of diseases including anaemia. One PHD inhibitor is approved for use for the treatment of renal anaemia and others are in late stage clinical trials. The number of reported templates for PHD inhibition is limited. We report structure–activity relationship and crystallographic studies on a promising class of 4‐hydroxypyrimidine‐containing PHD inhibitors., PHD candidates: The 2‐oxoglutarate‐dependent hypoxia inducible factor prolyl hydroxylases (PHDs) are targets for treatment of a variety of diseases including anaemia. One PHD inhibitor is approved for use for the treatment of renal anaemia and others are in late‐stage clinical trials. However, the number of reported templates for PHD inhibition is limited. We report structure‐activity relationship and crystallographic studies on a promising class of 4‐hydroxypyrimidine‐containing PHD inhibitors.
- Published
- 2019