Molecular basis for inhibiting human glucose transporters by exofacial inhibitors.

Human glucose transporters (GLUTs) are responsible for cellular uptake of hexoses. Elevated expression of GLUTs, particularly GLUT1 and GLUT3, is required to fuel the hyperproliferation of cancer cells, making GLUT inhibitors potential anticancer therapeutics. Meanwhile, GLUT inhibitor-conjugated insulin is being explored to mitigate the hypoglycemia side effect of insulin therapy in type 1 diabetes.

Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis.

The serine/threonine kinase SGK1 is an activator of the β-catenin pathway and a powerful stimulator of cartilage degradation that is found to be upregulated under genomic control in diseased osteoarthritic cartilage. Today, no oral disease-modifying treatments are available and chronic treatment in this indication sets high requirements for the drug selectivity, pharmacokinetic, and safety profile. We describe the identification of a highly selective druglike 1-pyrazolo[3,4-]pyrimidine SGK1 inhibitor that matches both safety and pharmacokinetic requirements for oral dosing.

A Palladium-Catalyzed Domino Reaction To Access 3-Amino-2-indazoles from Hydrazines and 2-Halobenzonitriles.

The development of a novel selective synthesis of 3-amino-2-indazoles from readily available 2-halobenzonitriles is presented. The reaction proceeds through a domino reaction sequence, consisting of a regioselective palladium-catalyzed coupling of monosubstituted hydrazines with 2-halobenzonitriles, followed by an intramolecular hydroamination through a 5-exo-dig cyclization and subsequent isomerization to directly afford a wide variety of substituted 2-indazole analogues in good to excellent yields.

Computational Investigation of Drug Phototoxicity: Photosafety Assessment, Photo-Toxophore Identification, and Machine Learning.

One of the most appreciated capabilities of computational toxicology is to support the design of pharmaceuticals with reduced toxicological hazard. To this end, we have strengthened our drug photosafety assessments by applying novel computer models for the anticipation of in vitro phototoxicity and human photosensitization. These models are typically used in pharmaceutical discovery projects as part of the compound toxicity assessments and compound optimization methods.

Sulfamide as Zinc Binding Motif in Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa).

Previously disclosed TAFIa inhibitors having a urea zinc-binding motif were used as the starting point for the development of a novel class of highly potent inhibitors having a sulfamide zinc-binding motif. High-resolution X-ray cocrystal structures were used to optimize the structures and reveal a highly unusual sulfamide configuration. A selected sulfamide was profiled in vitro and in vivo and displayed a promising ADMET profile.

G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges.

In this Perspective, recent advances and challenges in the development of GPR119 agonists as new oral antidiabetic drugs will be discussed. Such agonists are expected to exhibit a low risk to induce hypoglycemia as well as to have a beneficial impact on body weight. Many pharmaceutical companies have been active in the search for GPR119 agonists, making it a highly competitive area in the industrial environment.

Novel Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa) from Natural Product Anabaenopeptin.

Anabaenopeptins isolated from cyanobacteria were identified as inhibitors of carboxypeptidase TAFIa. Cocrystal structures of these macrocyclic natural product inhibitors in a modified porcine carboxypeptidase B revealed their binding mode and provided the basis for the rational design of small molecule inhibitors with a previously unknown central urea motif. Optimization based on these design concepts allowed for a rapid evaluation of the SAR and delivered potent small molecule inhibitors of TAFIa with a promising overall profile.

Discovery of N-[4-(1H-Pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides as Highly Active and Selective SGK1 Inhibitors.

From a virtual screening starting point, inhibitors of the serum and glucocorticoid regulated kinase 1 were developed through a combination of classical medicinal chemistry and library approaches. This resulted in highly active small molecules with nanomolar activity and a good overall in vitro and ADME profile. Furthermore, the compounds exhibited unusually high kinase and off-target selectivity due to their rigid structure.

Small Macrocycles As Highly Active Integrin α2β1 Antagonists.

Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2β1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin α2β1 with IC50s in the low nanomolar range. The conformation of the macrocycles was found to be highly important for the activity, and an X-ray crystal structure was obtained to clarify this.

The use of virtual screening and differential scanning fluorimetry for the rapid identification of fragments active against MEK1.

We report the analysis of an in-house fragment screening campaign for the oncology target MEK1. The application of virtual screening (VS) as a primary fragment screening approach, followed by biophysical validation using differential screening fluorimetry (DSF), with resultant binding mode determination by X-ray crystallography (X-ray), is presented as the most time and cost-effective combination of in silico and in vitro methods to identify fragments. We demonstrate the effectiveness of the VS-DSF workflow for the early identification of fragments to both 'jump-start' the drug discovery project and to complement biochemical screening data.

A general and mild domino approach to substituted 1-aminoindoles.

A versatile and efficient palladium catalyzed domino reaction leading to a broad range of substituted 1-aminoindoles has been developed. The title compounds were prepared from 2-halo-phenylacetylenes and simple hydrazines in good to excellent yields in just a few hours under mild conditions.

Mechanistic investigation of the 2,5-diphenylpyrrolidine-catalyzed enantioselective alpha-chlorination of aldehydes.

The mechanism for the 2,5-diphenylpyrrolidine-catalyzed enantioselective alpha-chlorination of aldehydes with electrophilic halogenation reagents has been investigated by using experimental and computational methods. These studies have led us to propose a mechanism for the reaction that proceeds through an initial N-chlorination of the chiral catalyst-substrate complex, followed by a 1,3-sigmatropic shift of the chlorine atom to the enamine carbon atom. The suggested reaction course is different from previously proposed mechanisms for organocatalytic enamine reactions, in which the carbon-electrophile bond is formed directly.

Organocatalytic asymmetric alpha-bromination of aldehydes and ketones.

The first organocatalytic enantioselective alpha-bromination of aldehydes and ketones is presented; a C2-symmetric diphenylpyrrolidine catalyst afforded the alpha-brominated aldehydes in good yields and up to 96% ee, while ketones were alpha-brominated by a C2-symmetric imidazolidine in up to 94% ee; furthermore, the organocatalytic enantioselective alpha-iodination of aldehydes is also demonstrated to proceed with up to 89% ee.

Novel imidazolidine-tetrazole organocatalyst for asymmetric conjugate addition of nitroalkanes.

The Michael addition of nitroalkanes to alpha,beta-unsaturated enones catalyzed by a novel chiral imidazolidine-2-yltetrazole organocatalyst has been investigated. The new more soluble organocatalyst decreases reaction times and improves enantioselectivities compared to other catalysts. The Michael addition adducts were obtained with up to 92% ee.

Direct organocatalytic asymmetric alpha-chlorination of aldehydes.

The direct organocatalytic enantioselective alpha-chlorination of aldehydes has been developed. The reaction proceeds for a series of different aldehydes with NCS as the chlorine source using easily available catalysts such as l-proline amide and (2R,5R)-diphenylpyrrolidine. The alpha-chloro aldehydes are obtained in up to 99% yield and up to 95% ee.

Direct asymmetric Michael reactions of cyclic 1,3-dicarbonyl compounds and enamines catalyzed by chiral bisoxazoline-copper(II) complexes.

The catalytic direct Michael addition of cyclic 1,3-dicarbonyl compounds and enamines to unsaturated 2-ketoesters is presented. A series of different 4-hydroxycoumarins, 4-hydroxy-6-methyl-2-pyrone, 3-hydroxy-1H-phenalene-1-one, 2-hydroxy-1,4-naphthoquinone, 5,5-dimethyl-1,3-cyclohexanedione, and various enamines of cyclic 1,3-diketones all add to unsaturated 4-substituted 2-ketoesters in an enantioselective manner. The reaction is catalyzed by chiral bisoxazoline-copper(II) complexes and proceeds in the absence of base to afford Michael adducts in good to high yields and with up to 98% ee.

Organocatalytic asymmetric conjugate addition of nitroalkanes to alpha,beta-unsaturated enones using novel imidazoline catalysts.

A new catalytic enantioselective conjugate addition of nitroalkanes to acyclic alpha,beta-unsaturated enones catalyzed by novel organic catalysts has been developed. A series of chiral amines has been tested as catalysts for the addition of 2-nitropropane to benzylideneacetone, and it is found that a novel imidazoline catalyst, prepared from phenylalanine, can catalyze a highly enantioselective 1,4-addition reaction. The reaction of various acyclic and cyclic nitroalkanes was found to proceed well with enantioselectivities up to 86% ee, and enantiopure products can be obtained by recrystallization.