Visible-Light-Enabled Aminocarbonylation of Unactivated Alkyl Iodides with Stoichiometric Carbon Monoxide for Application on Late-Stage Carbon Isotope Labeling.

A visible-light-mediated late-stage aminocarbonylation of unactivated alkyl iodides with stoichiometric amounts of carbon monoxide is presented. The method provides a mild, one-step route to [-C] alkyl amides, thereby reducing radioactive waste, and handling of radioactive materials. Easily accessible and low-cost equipment and a palladium catalyst were successfully used for the synthesis of a wide range of alkyl amides.

The synthesis of isotopologues of AZD7307: A selective β -adrenoreceptor agonist.

A medicinal chemistry program to develop potent and selective LABA compounds required the synthesis of both carbon-14 and stable-isotope labelled materials.  Carbon-14 labelled AZD7307 was successfully synthesised in 6 steps from [14C]chloroacetyl chloride in an overall radiochemical yield of 10%. In addition, the synthetic route of a stable labelled isotopomer of AZD7307 is also described and synthesised in four linear steps from [13C6]cyclohexylamine hydrochloride in an overall yield of 12%.

The synthesis of a tritium, carbon-14, and stable isotope-labeled cathepsin C inhibitors.

As part of a medicinal chemistry program aimed at developing a highly potent and selective cathepsin C inhibitor, tritium, carbon-14, and stable isotope-labeled materials were required. The synthesis of tritium-labeled methanesulfonate 5 was achieved via catalytic tritiolysis of a chloro precursor, albeit at a low radiochemical purity of 67%. Tritium-labeled AZD5248 was prepared via a 3-stage synthesis, utilizing amide-directed hydrogen isotope exchange.

The synthesis of tritium, carbon-14 and stable isotope labelled selective estrogen receptor degraders.

As part of a Medicinal Chemistry program aimed at developing an orally bioavailable selective estrogen receptor degrader, a number of tritium, carbon-14, and stable isotope labelled (E)-3-[4-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl]prop-2-enoic acids were required. This paper discusses 5 synthetic approaches to this compound class.

Syntheses of a radiolabelled CXCR2 antagonist AZD5069 and its major human metabolite.

The CXCR2 antagonist AZD5069 has been synthesized in tritium and carbon-14-labelled forms. [(3) H]AZD5069 was prepared via reductive dehalogenation of an iodinated precursor with tritium gas to provide material with a specific activity of 25.1 Ci/mmol.

The synthesis of [(14) C]AZD5122. Incorporation of an IV (14) C-microtracer dose into a first in human study to determine the absolute oral bioavailability of AZD5122.

AZD5122, N-(2-(2,3-difluorobenzylthio)-6-((2R,3R)-3,4-dihydroxybutan-2-ylamino)pyrimidin-4-yl)azetidine-1-sulfonamide was under investigation as a potential chemokine receptor CXCR2 antagonist for the treatment for inflammatory diseases. To gain a better understanding of the human pharmacokinetic profile, an exploratory phase I IV microtracer study was conducted using carbon-14 radiolabelled AZD5122. [(14) C]AZD5122 was carbon-14 labelled in the pyrimidine ring in five steps in an overall radiochemical yield of 19% from [(14) C]thiourea.

A short expedient synthesis of [(14)C]Ticlopidine.

To support the development of a reactive metabolite strategy, the preparation of several radiolabelled compounds such as [(14)C] Ticlopidine was required. In this report, we describe a facile and rapid synthesis of [(14)C] Ticlopidine starting from [(14)C] carbon dioxide. The compound was radiolabelled in the 2-chloromethyl portion of the molecule with a specific activity of 53.

Monocarboxylate transporter MCT1 is a target for immunosuppression.

Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1), using a strategy of photoaffinity labeling and proteomic characterization.