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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)
- Source :
- Journal of Medicinal Chemistry. 59:4859-4866
- Publication Year :
- 2016
- Publisher :
- American Chemical Society (ACS), 2016.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....9efaf5ebeeae34b71f735e8482dcb57c