Improving oral absorption of a rapidly crystallizing parent drug using prodrug strategy: Comparison of phosphate versus glycine based prodrugs.

With an increasing number of Biopharmaceutical Classification System (BCS) II/IV pipeline compounds, solubilizing and supersaturating formulation strategies are becoming prevalent. Beyond formulation and solid form strategies, prodrugs are also employed to overcome solubility-limited absorption of poorly water-soluble compounds. Prodrugs can potentially yield supersaturated systems upon conversion to the parent drug intraluminally and thus enhance absorption.

Discovery of Potent Azetidine-Benzoxazole MerTK Inhibitors with Target Engagement.

Inhibition of the receptor tyrosine kinase MerTK by small molecules has the potential to augment the immune response to tumors. Potent, selective inhibitors with high levels of target engagement are needed to fully evaluate the potential use of MerTK inhibitors as cancer therapeutics. We report the discovery and optimization of a series of pyrazinamide-based type 1.

Mining Medicinally Relevant Bioreduction Substrates Inspired by Ligand-Based Drug Design.

Exploring the scope of biocatalytic transformations in the absence of enzyme structures without extensive experimentation is a challenging task. To expand the limited substrate capacity of carrot-mediated bioreduction and hunt for new medicinally relevant ketones with minimum cost of labor and time, we deployed a practical method inspired by ligand-based drug design. Through analyzing collected literature data and building pharmacophore and reactivity prediction models, we screened a self-built virtual library of >8000 ketones bearing the most frequently used -heterocycles and functional groups in drug discovery.

Oxidation of Nonactivated Anilines to Generate -Aryl Nitrenoids.

A low-temperature, protecting-group-free oxidation of 2-substituted anilines has been developed to generate an electrophilic -aryl nitrenoid intermediate that can engage in C-NAr bond formation to construct functionalized -heterocycles. The exposure of 2-substituted anilines to PIFA and trifluoroacetic acid or 10 mol % Sc(OTf) triggers nitrenoid formation, followed by productive and selective C-NAr and C-C bond formation to yield spirocyclic- or bicyclic 3-indoles or benzazepinones. Our experiments demonstrate the breadth of these oxidative processes, uncover underlying fundamental elements that control selectivity, and demonstrate how the distinct reactivity patterns embedded in -aryl nitrenoid reactive intermediates can enable access to functionalized 3-indoles or benzazepinones.

Intramolecular Pd-Catalyzed Reductive Amination of Enolizable sp-C-H Bonds.

A palladium-catalyzed reductive cyclization of nitroarenes has been designed to construct sp-C-NHAr bonds from sp-C-H bonds by using an enolizable nucleophile to intercept a nitrosoarene intermediate. Exposure of -substituted nitroarenes to 5 mol % of Pd(OAc) and 10 mol % of phenanthroline under 2 atm of CO constructs partially saturated 5-, 6-, or 7-membered -heterocycles using α-pyridyl carboxylates, malonates, 1,3-dimethylbarbituric acid, 1,3-diones, or difurans as the nucleophile.

Rh(II)-Catalyzed Ring Expansion of Cyclobutanol-Substituted Aryl Azides To Access Medium-Sized N-Heterocycles.

A new reactivity pattern of Rh(II)-N-arylnitrenes was discovered that facilitates the synthesis of medium-sized N-heterocycles from ortho-cyclobutanol-substituted aryl azides. The key ring-expansion step of the catalytic cycle is both chemoselective and stereospecific. Our mechanistic experiments implicate the formation of a rhodium N-arylnitrene catalytic intermediate and reveal that sp C-H bond amination of this electrophilic species is competitive with the ring-expansion process.

Control of the Chemoselectivity of Metal N-Aryl Nitrene Reactivity: C-H Bond Amination versus Electrocyclization.

A mechanism study to identify the elements that control the chemoselectivity of metal-catalyzed N-atom transfer reactions of styryl azides is presented. Our studies show that the proclivity of the metal N-aryl nitrene to participate in sp-C-H bond amination or electrocyclization reactions can be controlled by either the substrate or the catalyst. Electrocyclization is favored for mono-β-substituted and sterically noncongested styryl azides, whereas sp-C-H bond amination through an H-atom abstraction-radical recombination mechanism is preferred when a tertiary allylic reaction center is present.

Mechanism of Rh2(II)-Catalyzed Indole Formation: The Catalyst Does Not Control Product Selectivity.

Possible mechanisms for Rh-promoted indole formation from vinyl/azidoarenes were examined computationally, and a mechanism is proposed in which the Rh catalyst promotes generation of a nitrene but is not directly involved in cyclization.

Assembly of functionalized carbocycles or N-heterocycles through a domino electrocyclization-[1,2] migration reaction sequence.

The development of processes that streamline the synthesis of complex, functionalized carbocycles and heterocycles remains a hotly pursued topic because their scaffolds are present in a range of bioactive molecules and electronic materials. Although the Nazarov reaction has emerged to be useful in the synthesis of carbocycles and heterocycles, using an electrocyclization to trigger a migration remains underdeveloped. By constructing several bonds in one operation, domino reaction sequences are particularly effective at improving the efficiency of synthesis.

Promoting Reductive Tandem Reactions of Nitrostyrenes with Mo(CO)6 and a Palladium Catalyst To Produce 3H-Indoles.

The combination of Mo(CO)6 and 10 mol % of palladium acetate catalyzes the transformation of 2-nitroarenes to 3H-indoles through a tandem cyclization-[1,2] shift reaction of in situ generated nitrosoarenes. Mo(CO)6 appears to have dual roles in this transformation: generate CO and promote C-N bond formation to increase the yield of the N-heterocycle product.

Development of a Suzuki cross-coupling reaction between 2-azidoarylboronic pinacolate esters and vinyl triflates to enable the synthesis of [2,3]-fused indole heterocycles.

The scope and limitations of a Suzuki reaction between 2-azidoarylboronic acid pinacolate esters and vinyl triflates are reported. This cross-coupling reaction enables the regioselective synthesis of indoles after a subsequent Rh(II)2-catalyzed sp(2)-C-H bond amination reaction.

Rh2(II)-catalyzed selective aminomethylene migration from styryl azides.

Rh(2)(II)-carboxylate complexes were discovered to promote the selective migration of aminomethylenes in β,β-disubstituted styryl azides to form 2,3-disubstituted indoles. Mechanistic data are also presented that suggest that the migration occurs stepwise before diffusion of the iminium ion.