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-<i>a</i>]­pyridine group of the previously reported inhibitor <b>3</b> with the related pyrazolo­[1,5-<i>a</i>]­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 (2<i>R</i>)-1-[4-(4-{[5-chloro-4-(pyrazolo­[1,5-<i>a</i>]­pyridin-3-yl)-2-pyrimidinyl]­amino}-3,5-dimethyl-1<i>H</i>-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, <b>28</b>), a novel, efficacious inhibitor of IGF-1R

Discovery of Novel 3‑Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase

A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (<b>4</b>), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1<i>R</i>)-1-(tetrahydro-2<i>H</i>-pyran-4-yl)­ethyl]­amino}-3-quinolinecarboxamide (<b>72</b>) and 7-fluoro-6-[6-(methoxymethyl)­pyridin-3-yl]-4-{[(1<i>S</i>)-1-(1-methyl-1<i>H</i>-pyrazol-3-yl)­ethyl]­amino}­quinoline-3-carboxamide (<b>74</b>) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. <b>72</b> and <b>74</b> constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model

Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target