Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction.

Myeloperoxidase is a promising therapeutic target for treatment of patients suffering from heart failure with preserved ejection fraction (HFpEF). We aimed to discover a covalent myeloperoxidase inhibitor with high selectivity for myeloperoxidase over thyroid peroxidase, limited penetration of the blood-brain barrier, and pharmacokinetics suitable for once-daily oral administration at low dose. Structure-activity relationship, biophysical, and structural studies led to prioritization of four compounds for in-depth safety and pharmacokinetic studies in animal models. One compound (AZD4831) progressed to clinical studies on grounds of high potency (IC50, 1.5 nM in vitro) and selectivity (>450-fold vs thyroid peroxidase in vitro), the mechanism of irreversible inhibition, and the safety profile. Following phase 1 studies in healthy volunteers and a phase 2a study in patients with HFpEF, a phase 2b/3 efficacy study of AZD4831 in patients with HFpEF started in 2021.

Subcutaneous delivery of a dendrimer-BH3 mimetic improves lymphatic uptake and survival in lymphoma.

As a malignant tumour of lymphatic origin, B-cell lymphoma represents a significant challenge for drug delivery, where effective therapies must access malignant cells in the blood, organs and lymphatics while avoiding off-target toxicity. Subcutaneous (SC) administration of nanomedicines allows preferential access to both the lymphatic and blood systems and may therefore provide a route to enhanced drug exposure to lymphomas. Here we examine the impact of SC dosing on lymphatic exposure, pharmacokinetics (PK), and efficacy of AZD0466, a small molecule dual Bcl-2/Bcl-xL inhibitor conjugated to a 'DEP®' G5 poly-l-lysine dendrimer. PK studies reveal that the plasma half-life of the dendrimer-drug conjugate is 8-times longer than that of drug alone, providing evidence of slow release from the circulating dendrimer nanocarrier. The SC dosed construct also shows preferential lymphatic transport, with over 50% of the bioavailable dose recovered in thoracic lymph. Increases in dose (up to 400 mg/kg) are well tolerated after SC administration and studies in a model of disseminated lymphoma in mice show that high dose SC treatment outperforms IV administration using doses that lead to similar total plasma exposure (lower peak concentrations but extended exposure after SC). These data show that the DEP® dendrimer can act as a circulating drug depot accessing both the lymphatic and blood circulatory systems. SC administration improves lymphatic exposure and facilitates higher dose administration due to improved tolerability. Higher dose SC administration also results in improved efficacy, suggesting that drug delivery systems that access both plasma and lymph hold significant potential for the treatment of haematological cancers where lymphatic and extranodal dissemination are poor prognostic factors.

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 [carbonyl-13/14C] 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.

Uptake and tissue accretion of orally administered free carboxylic acid as compared to ethyl ester form of docosahexaenoic acid (DHA) in the rat.

AIM: The aim of this study was to compare the plasma exposure and tissue accretion of docosahexaenoic acid (DHA) in response to oral dosing of free carboxylic acid (OM3CA) and ethyl ester (OM3EE) forms. MATERIALS AND METHODS: Sixteen adult male Wistar rats, fed a low-fat, carbohydrate-rich, standard chow diet, were chronically catheterized and gavaged for 5 consecutive days with either OM3CA (n = 9) or OM3EE (n = 7), the last day fasted overnight and spiked respectively with either 14C-DHA or 14C-DHA-ethyl ester (14C-DHA-EE) tracers. Appearance of 14C-labelled plasma polar and neutral lipids over 4 h and retention of 14C-activity (R) in the tissues at 4 h were measured. RESULTS: Compared to OM3EE, OM3CA resulted in 2- and 3-fold higher areas under the plasma 14C-labelled polar and neutral lipid curves (exposures), respectively, as well as, higher R in all tissues examined. For both OM3CA and OM3EE, R varied in a tissue specific manner; highest in liver, followed by red skeletal muscle, adipose tissue, brain and white skeletal muscle. Multiple linear regression analysis revealed that R in each tissue (except liver) was dependent on polar lipid exposure alone (r2>0.87 and P<0.001), but not neutral lipid exposure, and furthermore this dependence was indistinguishable for OM3CA and OM3EE. In the liver, R was found to be dependent on both polar and neutral lipid exposures (r2 = 0.97, P<0.001), with relative contributions of 85±2% and 15±2%, respectively. As for the other tissues, these dependencies were indistinguishable for OM3CA and OM3EE. CONCLUSION: The present results, in fasted low-fat diet fed rats, are consistent with higher oral bioavailability of OM3CA versus OM3EE forms of DHA. Once DHA has entered the circulation, the tissue distribution is independent of the dosed form and uptake in the skeletal muscle, fat and brain is driven by the polar pools of DHA in plasma, while DHA accretion in liver is supplied by both polar and neutral plasma lipids.

Toward molecular imaging of the free fatty acid receptor 1.

AIMS: Molecular imaging of the free fatty acid receptor 1 (FFAR1) would be a valuable tool for drug development by enabling in vivo target engagement studies in human. It has also been suggested as a putative target for beta cell imaging, but the inherent lipophilicity of most FFAR1 binders produces high off-target binding, which has hampered progress in this area. The aim of this study was to generate a suitable lead compound for further PET labeling. METHODS: In order to identify a lead compound for future PET labeling for quantitative imaging of FFAR1 in human, we evaluated tritiated small molecule FFAR1 binding probes ([3H]AZ1, [3H]AZ2 and [3H]TAK-875) for their off-target binding, receptor density and affinity in human pancreatic tissue (islets and exocrine) and rodent insulinoma. RESULTS: [3H]AZ1 showed improved specificity to FFAR1, with decreased off-target binding compared to [3H]AZ2 and [3H]TAK-875, while retaining high affinity in the nanomolar range. FFAR1 density in human islets was approximately 50% higher than in exocrine tissue. CONCLUSIONS: AZ1 is a suitable lead compound for PET labeling for molecular imaging of FFAR1 in humans, due to high affinity and reduced off-target binding.

Synthesis of 2 C-14 labeled cathepsin C inhibitors: The use of a cyanide to displace a Benzotriazole.

In support of the development of a new treatment for COPD, 2 C-14 labeled compounds were required for in vitro animal studies. The synthesis of nitrile [14 C]-1 was completed in 3 steps from C-14 labeled 4-bromobenzonitrile in accord with the previously developed medicinal chemistry route. The second compound, 2, did not possess an arylnitrile as did 1, which made the synthetic design more complex. An advanced, unlabeled benzotriazole containing intermediate, 10, was synthesized in low yield over 3 steps and was subsequently reacted with K14 CN to give a mixture of diastereomers 12. Separation of the diastereomers followed by deprotection afforded [14 C]-2 in a 13% radiochemical yield.

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. Carbon-14 and stable isotope-labeled AZD5248 were successfully prepared through modifications of the medicinal chemistry synthetic route, enabling the use of available labeled intermediates.

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.

Synthesis of [(3) H] and [(2) H6 ]AZD6642, an inhibitor of 5-lipoxygenase activating protein (FLAP).

An AstraZeneca effort to identify a 5-lipoxygenase activating protein inhibitor with good drug-like properties resulted in the identification of AZD6642. To further understand its drug metabolism and pharmacokinetic properties, it was required labeled with tritium. The tritiation of AZD6642 was effected by Ir-catalyzed exchange chemistry to give an average of one tritium per molecule. Additionally, a stable isotope labeled version of AZD6642 was required to support bioanalytical studies. The synthesis originated from [(2) H6 ]acetone which was converted to the trimethylsilyl cyanide adduct and subsequently reduced to give 2-(aminomethyl)-[1,1,1,3,3,3-(2) H6 ]propan-2-ol in good yield. Carbonylation to give an amide adduct resulted in an intermediate that was converted to the final compound in four steps.

Synthesis of ximelagatran, melagatran, hydroxymelagatran, and ethylmelagatran in H-3 labeled form.

In support of a study designed to better understand the liver toxicity of ximelagatran, ximelagatran, and melagatran, hydroxymelagatran and ethylmelagatran were prepared in tritium labeled form. Incorporation of tritium was achieved by hydrogen isotope exchange using Crabtree's catalyst and later with N-heterocyclic containing Ir catalyst. The tritiated product was then converted into the four target compounds to afford them in high purity and specific activity.

B-Alkylcatecholborane-mediated tandem radical conjugated addition-aldol cyclization.

A one-pot procedure involving radical conjugate addition of B-alkylcatecholboranes to enones followed by intramolecular aldol reaction is reported. Application to the stereoselective synthesis of monocyclic and bicyclic products with up to four contiguous stereogenic centers is presented.

Microwave-assisted group-transfer cyclization of organotellurium compounds.

Primary- and secondary-alkyl aryl tellurides, prepared by arenetellurolate ring-opening of epoxides/ O-allylation, were found to undergo rapid (3-10 min) group-transfer cyclization to afford tetrahydrofuran derivatives in 60-74% yield when heated in a microwave cavity at 250 degrees C in ethylene glycol or at 180 degrees C in water. To go to completion, similar transformations had previously required extended photolysis in refluxing benzene containing a substantial amount of hexabutylditin. The only drawback of the microwave-assisted process was the loss in diastereoselectivity which is a consequence of the higher reaction temperature. Substitution in the Te-aryl moiety of the secondary-alkyl aryl tellurides (4-OMe, 4-H, 4-CF(3)) did not affect the outcome of the group-transfer reaction in ethylene glycol. However, at lower temperature, using water as a solvent, the CF(3) derivative failed to react. The microwave-assisted group-transfer cyclization was extended to benzylic but not to primary- and secondary-alkyl phenyl selenides.

Radical carbonylation/reductive cyclization for the construction of tetrahydrofuran-3-ones and pyrrolidin-3-ones.

Beta-hydroxyalkyl aryl chalcogenides obtained by regioselective ring-opening of epoxides with benzeneselenolate or -tellurolate were found to undergo efficient hetero-Michael addition when treated with ethyl propiolate. Subsequent carbonylation/reductive cyclization of the resulting vinylogous carbonates in the presence of AIBN/TTMSS and carbon monoxide (80 atm) afforded 2,5-disubstituted tetrahydrofuran-3-ones, predominantly as cis isomers (cis/trans = 4/1-9/1). Starting from a polymer-supported diaryl diselenide, the methodology was also successfully extended to solid-phase synthesis. Vinylogous carbamates prepared by hetero-Michael addition of aziridines to electron-deficient alkynes were regioselectively ring-opened with benzeneselenolate from the sterically least hindered side. Radical carbonylation/reductive cyclization of the resulting N-vinyl-beta-amino-alkyl phenyl selenides afforded 2,5-disubstituted pyrrolidin-3-ones, predominantly as cis isomers (cis/trans = 3/1-12/1).

Construction of tetrahydrofuran-3-ones from readily available organochalcogen precursors via radical carbonylation/reductive cyclization.

[reaction: see text] beta-Hydroxyalkyl aryl chalcogenides, readily available by regioselective ring-opening of epoxides with nucleophilic benzeneselenolate or tellurolate, were O-alkylated by treatment with ethyl propiolate or (E)-1,2-bis(phenylsulfonyl)ethylene. Subsequent carbonylation/reductive cyclization in the presence of AIBN/TTMSS and carbon monoxide (80 atm) afforded tetrahydrofuran-3-ones in moderate to good yields.