Challenges of drug discovery in novel target space. The discovery and evaluation of PF-3893787: a novel histamine H4 receptor antagonist
Autor: | Emanuel Schenck, Wai L. Liu, Rhys M. Jones, Nick Clarke, Charlotte Alice Louise Lane, Michael Paradowski, Charles E. Mowbray, Michelle Collins, Mathew D. Selby, Andrew Simon Bell, David Howard Williams, Sandra D. Newman, Nigel Alan Swain |
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Rok vydání: | 2011 |
Předmět: |
Pyrrolidines
Drug discovery Organic Chemistry Clinical Biochemistry Antagonist Drug Evaluation Preclinical Histamine Antagonists Pharmaceutical Science Computational biology Biology Bioinformatics Biochemistry Rats Receptors G-Protein-Coupled Pyrimidines Drug Discovery Molecular Medicine Animals Humans Receptors Histamine Histamine H4 receptor Molecular Biology Receptors Histamine H4 |
Zdroj: | Bioorganicmedicinal chemistry letters. 21(21) |
ISSN: | 1464-3405 |
Popis: | We describe the development of novel benzimidazoles as small molecule histamine H4 receptor (H4R) antagonists and their profiling in rat early toxicity studies. The discovery and optimisation of a second series of pyrimidine based antagonists is then described culminating in the identification of the clinical development candidate 13 (PF-3893787). The pre-clinical profile of 13 (PF-3893787) is presented including the development of a translatable biomarker. Our pragmatic approach to target selection, safety assessment, and testing for efficacy faced numerous challenges and we share a number of lessons which the team learned and which will assist us and others in future drug discovery projects. |
Databáze: | OpenAIRE |
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