A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled.

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Retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) is a nuclear receptor that plays a major role in the production of interleukin (IL)-17. Considerable efforts have been directed toward the discovery of selective RORc inverse agonists as potential treatments of inflammatory diseases such as psoriasis and rheumatoid arthritis. Using the previously reported tertiary sulfonamide 1 as a starting point, we engineered structural modifications that significantly improved human and rat metabolic stabilities while maintaining a potent and highly selective RORc inverse agonist profile. The most advanced δ-sultam compound, GNE-3500 (27, 1-{4-[3-fluoro-4-((3S,6R)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone), possessed favorable RORc cellular potency with 75-fold selectivity for RORc over other ROR family members and >200-fold selectivity over 25 additional nuclear receptors in a cell assay panel. The favorable potency, selectivity, in vitro ADME properties, in vivo PK, and dose-dependent inhibition of IL-17 in a PK/PD model support the evaluation of 27 in preclinical studies.

New biphasic conditions for the palladium-catalyzed direct arylation of electron-poor fluorinated arenes have been developed. Taking advantage of biphasic chemistry, the use of an immiscible mixture of water and an organic solvent allows complete solubilization of all components of the system, enabling the reaction to proceed at room temperature in yields up to 99%.

The late stages of 30S and 50S ribosomal subunits biogenesis have been studied in a wild-type (wt) strain of Escherichia coli (MC4100) subjected to a severe heat stress (45–46°C). The 32S and 45S ribosomal particles (precursors to 50S subunits) and 21S ribosomal particles (precursors to 30S subunits) accumulate under these conditions. They are authentic precursors, not degraded or dead-end particles. The 21S particles are shown, by way of a modified 3′5′ RACE procedure, to contain 16S rRNA unprocessed, or processed at its 5′ end, and not at the 3′ end. This implies that maturation of 16S rRNA is ordered and starts at its 5′-terminus, and that the 3′-terminus is trimmed at a later step. This observation is not limited to heat stress conditions, but it also can be verified in bacteria growing at a normal temperature (30°C), supporting the idea that this is the general pathway. Assembly defects at very high temperature are partially compensated by plasmid-driven overexpression of the DnaK/DnaJ chaperones. The ribosome assembly pattern in wt bacteria under a severe heat stress is therefore reminiscent of that observed at lower temperatures in E. coli mutants lacking the chaperones DnaK or DnaJ.

New electron-deficient biarylphosphine ligands were studied and proved to be efficient for the direct arylation of heteroarenes with aryl iodides. The ability of a more electron-deficient palladium centre to accelerate the arylation of heterocycles that remained unreactive with aryl iodides in the past has been validated and these heteroarenes can now be smoothly reacted in the presence of a new electrophilic catalyst. Experimental evidence suggests a viable concerted metalation-deprotonation pathway for the C À H bond cleavage step with an electron-deficient palladium centre.Keywords: concerted metalation-deprotonation; direct arylation; heterocycles; palladium; phosphine ligands Heterocyclic biaryl compounds are predominant in natural products [1] and medicinal compounds.[2] Although the traditional methods to prepare these valuable motifs necessitate the use of a stoichiometric amount of organometallic coupling partner through transition metal catalysis, [3] more efficient processes in which the organometallic species can be replaced by a simple heteroarene have proven to be a viable alternative for the preparation of heteroatom-containing biaryls. [4,5] However, general conditions that are widely compatible with all classes of heterocyclic coupling partners are only sparsely reported [6] and the use of a different set of conditions for each class of substrate remains the norm. In order to further improve direct arylation and establish more broadly applicable reaction conditions, a better understanding of the reaction mechanism and the development of novel high-performance ligands are essential.As part of a program dedicated to the study of the direct arylation mechanism and the development of broadly applicable reaction conditions, we became interested in investigating the effect of electron-deficient phosphine ligands [7] on the C À H bond cleavage step of this process under Pd(0) catalysis. Whilst most of the focus has traditionally been on the study of electron-rich ligands, few studies on the effect of electron-deficient phosphine ligands are described in the literature.[4] Reports by Baudoin, [8] Gevorgyan [9] as well as our group [10] have validated the efficiency of electron-deficient ligands in intramolecular processes with Pd(0) catalysts. Additionally, new intermolecular reactions using p-accepting phosphite ligands have also been observed by Itami and co-workers under Rh(I) catalysis.[11]Herein, we report the development of a new class of electron-poor fluoroarylphosphine ligands that is compatible with a broad variety of heterocycles. We demonstrate that a more electron-deficient metal centre accelerates the direct arylation reaction and also report evidence that a concerted metalationdeprotonation (CMD) mechanism [12] is operative. These results should encourage further investigation of electron-deficient ligands in new transition metalcatalyzed transformations.In our initial ligand design studies, we focused our efforts toward the synthesis of biaryl-type phosphine ligands bearing elec...

The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series.