Identification and biological activity of 6-alkyl-substituted 3-methyl-pyridine-2-carbonyl amino dimethyl-benzoic acid EP4 antagonists
| Autor: | Daniel R. Mudra, Matthew J. Fisher, Maria-Jesus Blanco, Warshawsky Alan M, Xiao-Peng Yu, Tatiana Natali Vetman, Anita K. Harvey, Srinivasan Chandrasekhar, Xushan Wang, Kuklish Steven Lee, J.L. Oskins, Mark Chambers, C. Lin |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Stereochemistry Clinical Biochemistry Pharmaceutical Science Benzoates Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Diclofenac X-Ray Diffraction In vivo Drug Discovery Pyridine medicine Animals Molecular Biology IC50 Benzoic acid Whole blood Organic Chemistry Biological activity Rats 030104 developmental biology chemistry 030220 oncology & carcinogenesis Molecular Medicine Receptors Prostaglandin E EP4 Subtype Ex vivo medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:2303-2307 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2016.03.041 |
| Popis: | Continued SAR optimization of a series of 3-methylpyridine-2-carbonyl amino-2,4-dimethyl-benzoic acid led to the selection of compound 4f for clinical studies. Compound 4f showed an IC50 of 123nM for inhibition of PGE2-induced TNFα reduction in an ex vivo LPS-stimulated human whole blood assay (showing >10-fold increase over clinical compound CJ-023,423). Pharmacokinetic profile, selectivity and in vivo efficacy comparing 4f to NSAID diclofenac in the monoiodoacetic acid (MIA) pain model and adjuvant induced arthritis (AIA) inflammatory model are included. |
| Databáze: | OpenAIRE |
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