Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2-(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF-1R)
| Autor: | Sébastien L. Degorce, Franck Lach, Eva M. Lenz, Catherine B. Trigwell, Sarah L. Pass, Martin Pass, Clifford David Jones, Richard Ducray, Christopher Thomas Halsall, Scott Boyd, Jon Curwen |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Pyrimidine Pyridines Stereochemistry medicine.medical_treatment Administration Oral Mice Nude Pharmacology Crystallography X-Ray Cell Line Receptor IGF Type 1 Mice Structure-Activity Relationship 03 medical and health sciences Insulin-like growth factor chemistry.chemical_compound 0302 clinical medicine Drug Discovery Pyridine medicine Animals Potency Receptor Protein Kinase Inhibitors Ligand efficiency Dose-Response Relationship Drug Molecular Structure Kinase Bioavailability 030104 developmental biology chemistry 030220 oncology & carcinogenesis Pyrazoles Molecular Medicine Female |
| Zdroj: | Journal of Medicinal Chemistry. 59:4859-4866 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b00203 |
| Popis: | Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R. |
| Databáze: | OpenAIRE |
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