Pharmaron (United Kingdom)

Creatine, a naturally occurring guanidine carboxylic acid, serves as a critical energy metabolite in tissues with high energy demands. Certain cancers upregulate creatine metabolism to supplement their energy needs. Ompenaclid, a salt form of the well-studied creatine transporter inhibitor 3-guanidinopropionic acid (β-GPA), is in clinical development for the treatment of patients with colorectal tumors. Existing SLC6A8 inhibitors are low-potency molecules and frequently interact with related transporters. Herein, we report the discovery of SLC6A8 inhibitors with increased selectivity as well as in vitro and in vivo potency. A bioisostere approach was used by replacing the carboxylic acid of β-GPA with surrogate functional groups to achieve these improvements. Docking of these inhibitors into the recently published SLC6A8 cryo-EM structure reveals key binding contacts and supports the observed structure-activity relationships.

The discovery and process development for the synthesis of diastereopure sultam (1), a key chiral intermediate in route to a clinical candidate, are disclosed. Continuous route development to access (1) was required to satisfy both time and dynamic material needs during successive campaigns. Three distinct methods were developed to obtain diastereopure material. The first-generation process invoked time-intensive supercritical fluid chromatography (SFC) to access the diastereopure (2). Subsequent route development enabled a scalable, time-effective classical resolution approach that provided >20 kg of (1). Lastly, a Ruthenium-catalyzed diastereoselective hydrogenation approach was demonstrated on a hundred-gram scale and then coupled to the resolution technology to access (1), both reducing step count and improving overall yield relative to the resolution approach.

Malaria still standsout as one of the most devastating and prevalentdiseases globally, where the rise of resistance to different antimalarialdrugs in different regions has posed significant obstacles to globaltreatment and elimination. Consequently, there is a pressing needfor the development of new antimalarial agents with novel modes ofaction. In this study, we report the identification and optimizationof new indole-2-carboxamide derivatives where structural modificationshave yielded new compounds 6x with enhanced potency (Pf3D7-IC50 ∼ 0.3 μM) and improved metabolicstability (hMics = 3 μL/min/mg), while also minimizing the humanether-a-go-go-related gene (hERG, IC50 > 20 μM)channelactivity and cytotoxic effect on hepatic cells (CC50 >30 μM). Mode-of-action investigations revealed that a representativecompound from this series interfered with homeostasis of the parasite’sdigestive vacuole. However, cross-resistance was observed with resistantstrains, which was linked to efflux pumps such as Plasmodiumfalciparum chloroquine resistance transporter (PfCRT). Despite this challenge, these indole-2-carboxamidesprovide versatile molecular templates for innovative medicinal chemistryto overcome cross-resistance while maintaining other attractive propertiesof this novel series.

We report a modular strategy for the synthesis of trisubstituted chiral piperidines. First, a scalable, chiral-pool synthesis of an orthogonally protected piperidine tricarboxylic acid diester was developed. This synthesis involves a formal 4 + 2 cyclization between choro-homoserine and acetylene dicarboxylate, followed by a diastereoselective reduction, cyclic anhydride formation, and regioselective ring-opening process to give the final product as a single enantio- and diastereomer at >50 g scale. Next, we demonstrated that the piperidine tricarboxylate intermediate can undergo sequential decarboxylative functionalizations using modern transition metal-catalyzed or photocatalytic methodologies. As the result, highly elaborated chiral piperidines and pipecolic esters were prepared in a chemo- and stereoselective manner.

CD388 is a novel drug-Fc conjugate designed to function as a long-acting antiviral drug by inhibiting proliferation of the influenza virus. This action results from a dimeric form of zanamivir, a neuraminidase inhibitor, conjugated to an Fc fragment of recombinant human IgG1 through a noncleavable polyethylene glycol-based linker. In this study, we aimed to demonstrate that, although similar to monoclonal antibody-based molecules, CD388 is distinct in that it maintains stability in vivo for an extended period with minimal biotransformation and achieves prolonged exposure in the lungs, the intended site of therapeutic action. For this purpose, rats received a single subcutaneous administration of 146 mg/kg (655 μCi/kg) radiolabeled CD388 which resulted in a maximal plasma concentration at 24 hours and a terminal half-life of 190 hours. Drug-related radioactivity recovery in urine and feces over a 28-day period was 61% and 15% of the dose, respectively, with a total recovery of 96% ± 2% (cage wash, dose site, and carcass included). 14C-CD388-related radioactivity was distributed to most tissues and declined slowly beyond 120 hours, remaining widespread throughout the body during the entire sampling time (840 hours). During the period of absorption, the highest radioactivity was observed in the kidney, lung, cardiac blood, lymph duct, and lymph nodes. Based on liquid chromatography-accurate mass spectrometry data, CD388 was the major circulating component in plasma. Radioactivity observed in urine and feces were primarily metabolites containing unmodified dimeric zanamivir plus linker (abbreviated as di-ZAN). No free zanamivir was identified in the analyzed matrices. SIGNIFICANCE STATEMENT: CD388 is a drug-Fc conjugate in development for prevention of influenza. This study showed wide tissue distribution, prolonged clearance of CD388, and evidence that no zanamivir was cleaved from the drug-Fc conjugate. Catabolism of the Fc domain resulted in formation of metabolites containing the unmodified dimeric zanamivir plus linker. These data support the mode of action of CD388 and demonstrate that the conjugation of zanamivir to the Fc domain is stable, thereby enabling CD388 to maintain its potent antiviral activity.

We describe our approach to the total synthesis of AZD5991 (1) from a process development perspective through the complete redesign of our synthetic strategy from the ground up. The size and complexity of small-molecule therapeutic targets have continued to increase over recent decades. One such example, 1, is arguably the most complex active pharmaceutical ingredient (API) in AstraZeneca’s small molecule development portfolio to date and poses formidable synthetic challenges. The previous racemic synthesis of 1 was sufficient to supply early clinical activities; however, the route was not deemed commercially viable and had significant environmental challenges. The identification of a long-term sustainable route was therefore critical to enable the robust manufacture of drug substance for later clinical activities and launch. We report exploration of asymmetric approaches toward the atropisomeric core, new routes toward each of the four heterocyclic building blocks, including a divergent pyrazole functionalization, and final assembly in a scalable and controlled macrocyclization process. These improvements resulted in a 49% reduction in step count and 95% reduction in projected waste generation.

An intramolecular cyclization strategy to synthesize nitrogen-rich and biologically important 2-heteroaryl-indolin-3-ones has been developed in both batch and flow. Using high-throughput screening, citric acid in a dimethylformamide/water mixture was found to facilitate the reaction under batch conditions, which can tolerate substituted phenyl rings, quinolines, and naphthalenes with a variety of electronic and steric properties. The reaction was reoptimized for flow conditions using design of experiments, complementing the batch conditions for some substrates with greatly reduced reaction times.

Abstract The exploration of pyridine-directed C–H activation in 2-benzyl-6-phenylpyridine revealed selective bromination at the ortho-phenyl position via Rh catalysis, rather than the ortho-benzyl position. In contrast, the corresponding alkylation was unsuccessful, suggesting a preference for the Rh(III) pathway to minimize steric congestion from pyridine disubstitution. This mechanistic insight facilitated the development of a room-temperature C–H activation–bromination method, enabling the synthesis of a pyridine-pyridone α-helix mimic.