Oxyarylation and Aminoarylation of Styrenes Using Photoredox Catalysis

A three-component coupling of styrenes is reported, using photoredox catalysis to achieve simultaneous arylation and C–O or C–N bond formation across the styrene double bond

Benzylic C–H Azidation Using the Zhdankin Reagent and a Copper Photoredox Catalyst

An azidation method for C–N bond formation at benzylic C–H positions is described using copper-catalyzed visible light photochemistry and the Zhdankin azidoiodinane reagent. The method is applicable to a wide range of substrates bearing different functional groups and having a primary, secondary, or tertiary benzylic position, and is thought to proceed through a radical chain reaction

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

Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield <b>3</b>, which had modest CNS penetration. More significant progress was achieved by changing the core to give <b>40</b>, which combines good potency and CNS penetration. Compound <b>40</b> was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound <b>51</b>. This work casts doubt on the hypothesis that localized tissue modulation of 11β-HSD1 activity alleviates metabolic syndrome

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