Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design.

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures.

Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol.

The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs.

Tandem intramolecular photocycloaddition-retro-Mannich fragmentation as a route to spiro[pyrrolidine-3,3'-oxindoles]. Total synthesis of (+/-)-coerulescine, (+/-)-horsfiline, (+/-)-elacomine, and (+/-)-6-deoxyelacomine.

Irradiation of a tryptamine linked through its side-chain nitrogen to an alkylidene malonate residue results in an intramolecular [2 + 2] cycloaddition to the indole 2,3-double bond. The resultant cyclobutane undergoes spontaneous retro-Mannich fission to produce a spiro[indoline-3,3'-pyrrolenine] with relative configuration defined by the orientation of substituents in the transient cyclobutane. The tandem intramolecular photocycloaddition-retro-Mannich process, abbreviated as TIPCARM, leads to a spiropyrrolidine which is poised to undergo a second retro-Mannich fragmentation that expels the malonate unit and generates transiently an indolenine.

1-Benzylbenzimidazoles: the discovery of a novel series of bradykinin B(1) receptor antagonists.

The design, synthesis, and structure-activity studies of a novel series of BK B(1) receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B(1) receptor were discovered.

Quantum J1-J2 antiferromagnet on a stacked square lattice: influence of the interlayer coupling on the ground-state magnetic ordering.

Using the coupled-cluster method and the rotation-invariant Green's function method, we study the influence of the interlayer coupling Jperpendicular on the magnetic ordering in the ground state of the spin-1/2 J1-J2 frustrated Heisenberg antiferromagnet (J1-J2 model) on the stacked square lattice. In agreement with known results for the J1-J2 model on the strictly two-dimensional square lattice (Jperpendicular=0), we find that the phases with magnetic long-range order at small J2Jc2 are separated by a magnetically disordered (quantum paramagnetic) ground-state phase. Increasing the interlayer coupling Jperpendicular >0, the parameter region of this phase decreases, and, finally, the quantum paramagnetic phase disappears for quite small Jperpendicular approximately (0.