1. trans-Fluorine Effect in Cyclopropane: Diastereoselective Synthesis of Fluorocyclopropyl Cabozantinib Analogs
- Author
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Artis Kinens, Janis Veliks, Melita Videja, Raitis Bobrovs, Martins Priede, and Janis Kuka
- Subjects
Drug ,Cabozantinib ,010405 organic chemistry ,Drug discovery ,media_common.quotation_subject ,Organic Chemistry ,Diastereomer ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,In vitro ,0104 chemical sciences ,Cyclopropane ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Moiety ,Molecule ,media_common - Abstract
[Image: see text] Investigation of the trans-fluorine effect on the hydrolysis rate of diethyl 2-fluorocyclopropane-1,1-dicarboxylate provides synthetic access to both diastereomers of the fluorocyclopropyl analog of cabozantinib, a c-Met and VEGFR-2 inhibitor used as a first-line treatment for thyroid cancer and as a second-line treatment for renal cell carcinoma. Despite some known potent examples, there are only a few drug molecules that contain fluorocyclopropane moieties. Herein, we present a case study in which the monofluoro analog of a known cyclopropane-containing drug molecule displays an improved in vitro profile compared to the parent nonfluorinated structure. The fluorocyclopropane moiety may offer valuable fine-tuning options for lead optimization in drug discovery.
- Published
- 2020