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)
Copyright policy )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)
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.
- AstraZeneca (France) France
- ASTRAZENECA UK LIMITED United Kingdom
- AstraZeneca (United Kingdom) United Kingdom
Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Pyridines, Administration, Oral, Mice, Nude, Crystallography, X-Ray, Cell Line, Receptor, IGF Type 1, Mice, Structure-Activity Relationship, Drug Discovery, Animals, Pyrazoles, Female, Protein Kinase Inhibitors
Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Pyridines, Administration, Oral, Mice, Nude, Crystallography, X-Ray, Cell Line, Receptor, IGF Type 1, Mice, Structure-Activity Relationship, Drug Discovery, Animals, Pyrazoles, Female, Protein Kinase Inhibitors
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