α-Fluorination of tropane compounds and its impact on physicochemical and ADME properties

• Published in: Bioorganic & medicinal chemistry letters Vol. 108; p. 129798
• Main Authors: Hoshikawa, Tamaki, Kurokawa, Toshiki, Yoshimura, Hikaru, Shibuguchi, Tomoyuki
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2024; Elsevier
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; C-H functionalization; Cell Membrane Permeability - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Electrochemistry; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Ether-A-Go-Go Potassium Channels - metabolism; Fluorination; Halogenation; Humans; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Solubility; Structure-Activity Relationship; Tropanes - chemical synthesis; Tropanes - chemistry; Tropanes - pharmacology; Electrochemistry; C-H functionalization; Fluorination; C -H functionalization; QUANTITATIVE ASSESSMENT
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129798

[Display omitted] Using an electrochemical C(sp3)-H fluorination reaction, a series of α-fluorinated tropane compounds were synthesized and their druglikeness parameters were assessed to compare with the parent compounds. Improvements were observed in membrane permeability, P-gp liability, and inhibitory effects on hERG and Nav1.5 channels, accompanied with a trend of decreased aqueous solubility and microsomal stability. It was also revealed that α-fluorination reduced the basicity of tropane nitrogen atom for about 1000-fold.