J. Ramphal, J. B. Nicholas, C. Schaefer, H. Ramesha, L. Hooi, A. Arfsten, K. Kossen, D. Ruhrmund, S. Lim, S. Kim, K. Dolim, C. Zhen, M. Hu, J. Henshilwood, R. Radhakrishnan, S. Sastry, K. Emayan, S. Misialek, R. Rajagopalan, L. Pan, L. Huang, S. Yap, S. D. Seiwert, B. O. Buckman InterMune, Inc., Brisbane, CA, USA Background: Pirfenidone is an orally active small molecule antifibrotic agent that has been approved for the treatment of IPF in multiple countries in Europe, Asia, North America and Latin America. Therefore, pirfenidone can be viewed as one of the few clinically validated chemotypes for IPF treatment. Further optimization of the pirfenidone chemotype was undertaken for ADME/PK, efficacy and safety properties. Methods : A library of analogs based on chemical similarity to pirfenidone was designed and screened in anti-fibrotic, cell-based assays. Results : Across animal species, oral dosing of ITMN-14440 provided greater drug exposure at lower relative Cmax than pirfenidone. In a 14-day bleomycin-induced pulmonary fibrosis model with prophylactic dosing, and in a 28-day model with therapeutic dosing, ITMN-14440 had improved efficacy, and anti-fibrotic activity was observed at lower doses and with less frequent dosing when compared to pirfenidone. In a rodent model with potential relevance to the gastrointestinal side effects, ITMN-14440 showed superior performance relative to pirfenidone. Conclusions: Optimized analogs of pirfenidone represent novel chemical entities that may advance the treatment of IPF and other fibrotic conditions. ITMN-14440 displays superior performance relative to pirfenidone in animal models of pulmonary fibrosis and minimal effects in a model of gastrointestinal side effects. The non-clinical pharmacokinetic properties of ITMN-14440 suggest the potential for once or twice daily dosing in humans.
Icosapentaenoic acids and their metabolites are of both nutritional and bio-medical interest. The title compounds were previously accessible in only very small amounts via biosynthetic routes. Their first total synthesis has now been achieved in good yield and in a stereocontrolled fashion. The key steps were a Pd0–Cu1-catalyzed coupling of terminal alkynes with vinyl halides to give the icosanoid skeleton and Lindlar hydrogenation to give the Z olefins.
Abstract Among the various enzymes found in human tissues that act on arachidonic acid, there are three major types of lipoxygenases (LO), operating at the 5‐, 12‐, and 15‐positions. The 5‐LO is a key enzyme and plays a central role in the biosynthesis of leukotrienes, which are potent arachidonate‐derived mediators of allergy and inflammation. Because of the importance of the 5‐LO‐derived products in human pathophysiology, studies were initiated to examine the consequences of initial lipoxygenation at C15 of arachidonic acid as well as to probe interactions between the major LO pathways. These studies led to the identification of a new series of biologically active tetraene‐containing eicosanoids termed lipoxins. This article summarizes the isolation, biosynthesis, and chemical synthesis of lipoxins and related systems, and reviews recent results concerning their formation and biological activities. The total synthesis of these molecules based on a new and general synthetic strategy involving palladium catalysis is reviewed. This synthetic approach has allowed the preparation of several types of acyclic eicosanoids in their naturally occurring forms which, in turn, allowed comparisons with naturally derived materials and enabled detailed studies of the biological actions of these biomolecules. Structure–activity relationships were also derived by combining chemical synthesis and biological investigations.
Icosapentaensäuren und ihre Metabolite interessieren sowohl unter ernährungsphysiologischen als auch unter biomedizinischen Aspekten. Die Titelverbindungen waren bisher nur biosynthetisch in kleinsten Mengen erhältlich. Die erste Totalsynthese gelang nun stereokontrolliert in guten Ausbeuten. Schlüsselschritte waren eine Pd°-Cu1-katalysierte Kupplung terminaler Alkine mit Vinylhalogeniden zum Icosanoid-Gerüst und die Lindlar-Hydrierung zum Z-Olefin.
