title: 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).
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.
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.|Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
authors.forename: Sébastien L
authors.initials: SL
authors.lastname: Degorce
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Scott
authors.initials: S
authors.lastname: Boyd
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Jon O
authors.initials: JO
authors.lastname: Curwen
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Ducray
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Halsall
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.|Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Jones
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Lach
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Lenz
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Pass
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pass
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Trigwell
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000619429:AZD9362; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D017526:Receptor, IGF Type 1