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RORγt, an isoform of the retinoic acid-related orphan receptor gamma (RORc, RORγ), has been identified as the master regulator of T-helper 17 (TH 17) cell function and development, making it an attractive target for the treatment of autoimmune diseases. Validation for this target comes from antibodies targeting interleukin-17 (IL-17), the signature cytokine produced by TH 17 cells, which have shown impressive results in clinical trials. Through focused screening of our compound collection, we identified a series of N-sulfonylated benzoxazepines, which displayed micromolar affinity for the RORγ ligand-binding domain (LBD) in a radioligand binding assay. Optimization of these initial hits resulted in potent binders, which dose-dependently decreased the ability of the RORγ-LBD to interact with a peptide derived from steroid receptor coactivator 1, and inhibited the release of IL-17 secretion from isolated and cultured human TH 17 cells with nanomolar potency. A cocrystal structure of inverse agonist 15 (2-chloro-6-fluoro-N-(4-{[3-(trifluoromethyl)phenyl]sulfonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide) bound to the RORγ-LBD illustrated that both hydrophobic interactions, leading to an induced fit around the substituted benzamide moiety of 15, as well as a hydrogen bond from the amide NH to His479 seemed to be important for the mechanism of action. This structure is compared with the structure of agonist 25 (N-(2-fluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-6-amine ) and structures of other known RORγ modulators.

Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger-loop inhibitors based on a thieno[3,2-b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N-acetamides with submicromolar potency in the cell-based replicon assay, but they lacked oral bioavailability in rats. By linking the N4-position to the ortho-position of the C5-aryl group, we were able to identify the tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger-loop inhibitors based on an indole scaffold.

Few structures of viral serine proteases, those encoded by the Sindbis and Semliki Forest viruses, hepatitis C virus (HCV) and cytomegalovirus, have been reported. In the life cycle of HCV a crucial role is played by a chymotrypsin-like serine protease encoded at the N–terminus of the viral NS3 protein, the solution structure of which we present here complexed with a covalently bound reversible inhibitor. Unexpectedly, the residue in the P2 position of the inhibitor induces an effective stabilization of the catalytic His–Asp hydrogen bond, by shielding that region of the protease from the solvent. This interaction appears crucial in the activation of the enzyme catalytic machinery and represents an unprecedented observation for this family of enzymes. Our data suggest that natural substrates of this serine protease could contribute to the enzyme activation by a similar induced-fit mechanism. The high degree of similarity at the His–Asp catalytic site region between HCV NS3 and other viral serine proteases suggests that this behaviour could be a more general feature for this category of viral enzymes.

The synthesis of the monoterpene (+)-artemeseole (1b) is accomplished by starting from (Z)-dienol 5. Sharpless epoxidation of 5 gives oxirane 4. Attempted opening of the epoxide ring in 4 or in derivatives 8a, b by various allyl or acetylide anions gives side reactions, but the desired coupling with a C3 unit is achieved in the reaction of silyl-protected oxirane 8b with 9 or 13 giving 17 and 19a, respectively. Alkenol 19a is further converted into oxirane 21 by desilylation, tosylation, and base-induced epoxide formation. Anion generation from 21 by reductive desulfurization yields (dialkenylcyclopropyl)methanol 3. Acid-catalyzed cyclization to a tetrahydrofuran completes the synthesis of 1b.

The title compounds are prepared by an efficient one-pot reaction involving ring-opening of an epoxide with lithium 3-trimethylsilyl-1-phenylthio-2-propyn-1-ide, tosylation of the intermediate alkoxide and finally deprotonation. Anan alternative approach, intramolecular epoxide ring opening by a β anion is succesfully applied

Vinylcyclopropanes 5,9,10 are conveniently obtained by sulfur-mediated SNi reactions.

The cis-fused tricyclic dienone 13 is the major product formed from intramolecular Heck cyclization of the dienyl triflate 12 (Scheme I). Similarly, the cis-hexahydrophenanthridine 22 is formed in good yield from Heck cyclization of the aryl triflate 21. This latter conversion demonstrates that allylic ether substitution is compatible with intramolecular Heck chemistry and suggests applications of this chemistry in the synthesis of highly oxidized cardenolides.

A convenient modular synthesis for the construction of densely functionalized thieno[3,2-b]pyrroles, allosteric inhibitors of the Hepatitis C virus NS5B polymerase, is described. The route allows the introduction of substituents in positions 4, 5, and 6 of the thienopyrrole scaffold and can also be applied to the regioisomeric thieno[2,3-b]pyrrole core.

We report a new series of inhibitors for hepatitis C virus NS5B RNA polymerase containing a constrained pentacyclic scaffold. Our SAR studies led to the identification of hexahydroindolo[2,1-a]pyrrolo[3,2-d][2]benzazepines exposing basic groups. The compounds displayed a high activity in the enzyme assay and displayed good activity in the cell-based (replicon) assay in the presence of serum proteins.

Synthesis of rac-Norartemeseol The synthesis of the terpenoid rac-norartemesol (1b) is accomplished using epoxide ring-opening reactions as key steps. Thus, addition of the thio-substituted allyl anion 2b to ethylene oxide followed by proton-induced cyclisation provides the tetrahydrofuran 4a. The oxirane 6, which is formed by simple functional group interconversion, is opened by the diethylaluminium salt 10 of a propargylsilane. After catalytic hydrogenation and tosylation, fluoride-induced cyclisation of the allylsilane 13 gives the target molecule 1b.

A variety of ethyl 1-substituted 2-aryl-5-ethoxy-6-oxo-l,6-dihydropyrimidine-4-carboxylates were synthesized by efficient thermal or microwave-promoted Suzuki coupling of 2-chloroN1-substituted precursors.

5,6-Dihydroxypyrimidine-4-carboxylic acids are a promising series of hepatitis C virus (HCV) NS5B polymerase inhibitors that bind at the active site of the enzyme. Here we report a simple 2-thienyl substituted analogue that shows 10-fold improved activity over the original lead, and which allowed us to further delineate the key elements of the pharmacophore of this class of inhibitor. This work led to the identification of a trifluoromethyl acylsulfonamide group as a viable replacement for the C4 carboxylic acid in this series.