The syntheses of [¹⁴C]BMS‐823778 for use in a human ADME clinical study and of [¹³CD₃¹³CD₂]BMT‐094817, a stable‐isotope labeled standard of a newly detected human metabolite

Abstract

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-823778 as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon-14-labeled material was required for use in a human adsorption, distribution, metabolism, and excretion (ADME) study. The HCl salt form of [(14) C]BMS-823778 was synthesized in two steps from commercially available [2-(14) C]acetone. The radiochemical purity of the synthesized [(14) C]BMS-823778 after dilution with unlabeled clinical-grade BMS-823778 was 99.5% having a specific activity of 7.379 μCi/mg. One result of the human ADME study was the detection of a new human metabolite, BMT-094817. To support the quantification of BMT-094817 in clinical samples, it was necessary to synthesize [(13) CD3 (13) CD2 ]BMT-094817 for use as a liquid chromatography/mass spectrometry standard. [(13) CD3 (13) CD2 ]BMT-094817 was prepared in five labeled steps from [(13) CD3 ]iodomethane.

Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β‐hydroxysteroid dehydrogenase type‐1 inhibitor BMS‐823778

“…BMS‐823778, M1 (hydroxylated metabolite of BMS‐823778), [ 14 C]BMS‐823778 (72.5 μCi/mg) and [ 13 C 2 , D 6 ]BMS‐823778 were supplied by the Department of Chemistry, Bristol‐Myers Squibb (Princeton, NJ, USA) . β‐nicotinamide adenine dinucleotide phosphate‐reduced form (β‐NADPH), uridine 5′‐diphospho‐glucuronic acid (UDPGA) and alamethicin were obtained from Sigma‐Aldrich Co. (St Louis, MO, USA).…”

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

“…13 The incorporation of 14 C, 13 C or 11 C (*C) units into drug molecules or precursors by the formation of a *C-C bond is challenging and often requires revised synthetic pathways to introduce the label from *CO, 14-18 *CH3I, [19][20] or other small molecules derived by reduction of *CO2. [21][22][23][24][25] The direct exchange of carboxylate groups with CO2 offers the potential for simple and cost-effective syntheses of C-labelled small molecules, particularly as CO2 (or BaCO3) is the feedstock for all radiolabelled carbon-based precursors. 26 The easy conversion of carboxylic acids into other common functionalities (esters, amides, ketones, alcohols) makes this an attractive tactic for isotope incorporation.The use of redox active hydroxyphthalimide ester substrates in combination with Ni-based mediators and stoichiometric metal reductants enables carboxylate groups to undergo net exchange with CO2 (Fig 1A ).…”

“…Metal-catalyzed 1 H/ 3 H exchange is widely used in drug development to introduce long-lived radiolabels into target molecules. − The loss of 3 H labels through (bio)­chemical reactions and metabolic shifting due to primary kinetic isotope effects are liabilities of 3 H-labeling approaches. , ADME tracer compounds with greater stability can be obtained by using 14 C radiolabels . Similarly, 11 C isotopologues of native bioactive molecules enable PET probe generation without changes to their biological or pharmacological properties. , The incorporation of 14 C, 13 C, or 11 C (*C) units into drug molecules or precursors by the formation of a *C–C bond is challenging and often requires revised synthetic pathways to introduce the label from *CO, − *CH 3 I, , or other small molecules derived by reduction of *CO 2 . − The direct exchange of carboxylate groups with CO 2 offers the potential for simple and cost-effective syntheses of C-labeled small molecules, particularly as CO 2 (or BaCO 3 ) is the feedstock for all radiolabeled carbon-based precursors . The easy conversion of carboxylic acids into other common functionalities (esters, amides, ketones, alcohols) makes this an attractive tactic for isotope incorporation.…”

The syntheses of [13C6] and [phenyl‐14C(U)]BMS‐816336, an inhibitor of 11β‐hydroxysteroid dehydrogenase type 1, for type 2 diabetes

“…To further the development of BMS‐816336, it was necessary to prepare [phenyl‐ 14 C(U)]BMS‐816336 for metabolic profiling and stable‐isotope labeled BMS‐816336 for use as a liquid chromatography/mass spectrometry (LC/MS) standard. Radiolabeled and stable‐isotope labeled BMS‐816336 represent the third in a series of labeled Bristol‐Myers Squibb assets in the 11β‐HSD1 inhibitor class of compounds …”