Sharada Shenvi Labadie

Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2.

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

De Novo Fragment Design: A Medicinal Chemistry Approach to Fragment-Based Lead Generation

The use of fragments with low binding affinity for their targets as starting points has received much attention recently. Screening of fragment libraries has been the most common method to find attractive starting points. Herein, we describe a unique, alternative approach to generating fragment leads. A binding model was developed and a set of guidelines were then selected to use this model to design fragments, enabling our discovery of a novel fragment with high LE.

3-Aryl-2,4-pentanediones from 3,5-Dimethyl-4-iodoisoxazoles: An Application of a Palladium-Catalyzed Cross-Coupling Reaction

Abstract 3,5-Dimethyl-4-iodoisoxazole readily undergoes palladium-catalyzed coupling with arylboronic acids and organostannanes to form 4-aryl-3,5-dimethylisoxazoles. The unique nature of the isoxazole-ring is exploited to convert 4-aryl-3,5-dimethylisoxazoles to 3-aryl-2,4-pentanediones.

Discovery of N-[4-[6-tert-Butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]phenyl]methanesulfonamide (RG7109), a Potent Inhibitor of the Hepatitis C Virus NS5B Polymerase

In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.

Utility of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine. An efficient solid-phase synthesis of olomoucine

4,6-Dichloro-2-(methylthio)-5-nitropyrimidine has been utilized as a building block for an efficient nine-step synthesis of olomoucine. The methodology reported herein is applicable to the regiocontrolled solution and solid-phase synthesis of libraries of highly substituted purines, as well as other related scaffolds.

A novel series of IKKβ inhibitors part I: Initial SAR studies of a HTS hit.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.

Synthesis of purine derivatives

The methylation of 2-chloro-7-methylhypoxanthine in aqueous alkali forms, as well as 2-chloro-1,7-dimethylhypoxanthine, two isomers of this compound. These isomers were isolated and characterized as 2 chloro-3,7-dimethylhypoxanthine and 2 chloro-6-oxo-7, 9-dimethylpurine betaine.

A novel series of IKKβ inhibitors part II: description of a potent and pharmacologically active series of analogs.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.

Efficient Synthesis of Hexahydrocarbazoles

Abstract Selective reduction of the nitro group in methyl 1-(2-nitrophenyl)-4-oxo-cyclohex-2-enecarboxylates with zinc-acetic acid forms hexahydrocarbazoles. The reaction is applicable to the corresponding pyridyl analogs to generate azahexahydrocarbazoles. This provides an efficient method for the generation of tricyclic framework.

Facile Synthesis of Spiro Oxindoles, Azaoxindoles, and Dihydroisoquinolone

Abstract Formation of 1-aryl-4-oxo-cyclohexa(e)nonecarboxylates from the Diels–Alder cycloaddition of 2-trimethylsilyloxy-1,3-butadiene and Danishefsky diene with aryl- and pyridylacrylates and further conversion thereof to spirocycles is described. This provides an efficient method for spiro oxindoles, azaoxindoles, and dihydroisoquinolones.