Peter A. Blomgren

Biaryls via Suzuki Cross-Couplings Catalyzed by Nickel on Charcoal

Abstract Using the heterogeneous catalyst ‘Ni/C’, biaryl bonds can be made between functionalized aryl chlorides and boronic acids in good isolated yields. A standard set of conditions has been developed which applies to a variety of reaction partners.

Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase.

Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose-limiting adverse effects that have been attributed, at least in part, to the off-target activities of 1. It is expected that a more selective Syk inhibitor would provide a greater therapeutic window. Herein we report the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identification of GS-9973, 68, a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications.

Kumada couplings catalyzed by nickel on charcoal (Ni/C)

Abstract Carbon–carbon bond-forming reactions between aryl chlorides and Grignard reagents can be catalyzed under heterogeneous conditions using nickel on charcoal.

SUBSTITUTION REACTIONS OF ARYL CHLORIDES WITH ORGANOZINC REAGENTS CATALYZED BY NI(0)

Abstract Treatment of substituted aryl chlorides with functionalized organozinc iodides in the presence of catalytic amounts of a soluble Ni(0) source lead to efficient displacement reactions.

Nickel(0)-catalyzed couplings of vinyl- alanes & - zirconocenes with chloromethylated heteroaromatics: A route to E-allylated heterocycles

Abstract Treatment of selected chloromethylated heteroaromatics, including pyridines, thiophenes, and furans, with vinyl alanes or vinyl zirconocenes in the presence of Ni(0) results in E-allylated products in good yields.

Btk-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell–associated damage in IFNα-driven lupus nephritis

Systemic lupus erythematosus (SLE) is often associated with exaggerated B cell activation promoting plasma cell generation, immune-complex deposition in the kidney, renal infiltration of myeloid cells, and glomerular nephritis. Type-I IFNs amplify these autoimmune processes and promote severe disease. Brutons tyrosine kinase (Btk) inhibitors are considered novel therapies for SLE. We describe the characterization of a highly selective reversible Btk inhibitor, G-744. G-744 is efficacious, and superior to blocking BAFF and Syk, in ameliorating severe lupus nephritis in both spontaneous and IFNα-accelerated lupus in NZB/W_F1 mice in therapeutic regimens. Selective Btk inhibition ablated plasmablast generation, reduced autoantibodies, and - similar to cyclophosphamide - improved renal pathology in IFNα-accelerated lupus. Employing global transcriptional profiling of spleen and kidney coupled with cross-species human modular repertoire analyses, we identify similarities in the inflammatory process between mice and humans, and we demonstrate that G-744 reduced gene expression signatures essential for splenic B cell terminal differentiation, particularly the secretory pathway, as well as renal transcriptional profiles coupled with myeloid cell-mediated pathology and glomerular plus tubulointerstitial disease in human glomerulonephritis patients. These findings reveal the mechanism through which a selective Btk inhibitor blocks murine autoimmune kidney disease, highlighting pathway activity that may translate to human SLE.