2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2016 May 26;59(10):4859-66. doi: 10.1021/acs.jmedchem.6b00203.
Sébastien L Degorce 1 2,  Scott Boyd 1,  Jon O Curwen 1,  Richard Ducray 2,  Christopher T Halsall 1,  Clifford D Jones 1 2,  Franck Lach 2,  Eva M Lenz 1,  Martin Pass 1,  Sarah Pass 1,  Catherine Trigwell 1
Affiliations

Affiliations

  • 1 Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • 2 Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
PMID: 27078757 DOI: 10.1021/acs.jmedchem.6b00203
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.

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