ABSTRACT
Inhibition of the sodium-glucose cotransporter 2 (SGLT2) by canagliflozin in type 2 diabetes mellitus results in large between-patient variability in clinical response. To better understand this variability, the positron emission tomography (PET) tracer [18F]canagliflozin was developed via a Cu-mediated 18F-fluorination of its boronic ester precursor with a radiochemical yield of 2.0 ± 1.9% and a purity of >95%. The GMP automated synthesis originated [18F]canagliflozin with a yield of 0.5-3% (n = 4) and a purity of >95%. Autoradiography showed [18F]canagliflozin binding in human kidney sections containing SGLT2. Since [18F]canagliflozin is the isotopologue of the extensively characterized drug canagliflozin and thus shares its toxicological and pharmacological characteristics, it enables its immediate use in patients.
Subject(s)
Canagliflozin/chemical synthesis , Fluorine Radioisotopes , Molecular Imaging/methods , Positron-Emission Tomography/methods , Sodium-Glucose Transporter 2 Inhibitors/chemical synthesis , Sodium-Glucose Transporter 2/analysis , Humans , Radioactive TracersABSTRACT
Canagliflozin (Invokana, JNJ-28431754) is an orally bioavailable and selective SGLT2 (subtype 2 sodium-glucose transport protein) inhibitor approved for the treatment of type 2 diabetes. Herein, we report the synthesis of 13 C and 14 C-labeled canagliflozin. Stable isotope-labeled [13 C6 ]canagliflozin was synthesized in 4 steps starting from [13 C6 ]-labeled glucose. The [14 C]-Labeled canagliflozin was synthesized by incorporation of [14 C] into the benzylic position between the thiophene and benzene rings of the compound. Detailed synthesis of the isotope-labeled compounds is reported.
Subject(s)
Canagliflozin/chemistry , Canagliflozin/chemical synthesis , Sodium-Glucose Transporter 2 Inhibitors , Canagliflozin/pharmacology , Carbon Isotopes/chemistry , Carbon Radioisotopes/chemistry , Chemistry Techniques, Synthetic , Isotope LabelingABSTRACT
The diastereoselective addition of organozinc species to 1,2-anhydro sugars in toluene/n-dibutyl ether solvent is reported. Compared to the existing methods, the reaction proceeds at 0 °C, and only a slight excess of nucleophile is required to achieve good yields. Scope was assessed with different O-protected glycals along with various nucleophiles (aryl, alkynyl). This methodology was applied to the synthesis of the α-anomer of canagliflozin.
Subject(s)
Alkynes/chemistry , Canagliflozin/chemical synthesis , Ethers/chemistry , Glycosides/chemical synthesis , Monosaccharides/chemical synthesis , Toluene/chemistry , Canagliflozin/chemistry , Glycosides/chemistry , Monosaccharides/chemistry , StereoisomerismABSTRACT
The ß-selective phenylation of benzyl and boronate protected 1,6-anhydroglucose and the direct phenylation of unprotected 1,6-anhydroglucose (10), pretreated with i-Bu2AlH, i-Bu3Al, Et3Al, Me3Al, or n-octyl3Al, with triphenylalane or aryl(chloro)alanes is reported. The utility of the unprotected version of the method is demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin (1a), from commercially available 10 in one C-C bond-forming step. This approach circumvents the need for conventional protecting groups, and therefore no formal protection and deprotection steps are required.
