Seletracetam

The introduction of fluorine‐containing groups into organic molecules can significantly affect their physical and chemical properties and has long been used as an effective strategy for drug discovery and development. Consequently, the development of catalytic asymmetric methods for the synthesis of fluorine‐containing heterocycles is highly desirable and sought after. Herein, we describe a nickel‐catalyzed defluorinative asymmetric cyclization of fluoroalkyl‐substituted 1,6‐enynes, providing an expedient access to synthetically attractive 4‐fluorovinyl‐substituted 2‐pyrrolidones in good yields with remarkable high levels of chemo‐, regio‐, and enantioselectivities (90–99 % ee,>35 examples). This protocol features readily available starting materials and excellent functional group compatibility, and exhibits complementary regioselectivity. The utility of this strategy was demonstrated in the enantioselective synthesis of the antiepileptic drug Seletracetam.

Cathepsin C (CatC) is a dipeptidyl-exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N-terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive protease activities in various neutrophil mediated diseases. We designed and synthesized a series of dipeptidyl cyclopropyl nitrile compounds as putative CatC inhibitors. One compound, IcatC_XPZ-01 ((S)-2-amino-N-((1R,2R)-1-cyano-2-(4'-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4-yl)cyclopropyl)butanamide)) was identified as a potent inhibitor of both human and rodent CatC. In mice, pharmacokinetic studies revealed that IcatC_XPZ-01 accumulated in the bone marrow reaching levels suitable for CatC inhibition. Subcutaneous administration of IcatC_XPZ-01 in a monoclonal anti-collagen antibody induced mouse model of rheumatoid arthritis resulted in statistically significant anti-arthritic activity with persistent decrease in arthritis scores and paw thickness.