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Prodrugs are derivatives with superior properties compared with the parent active pharmaceutical ingredient (API), which undergo biotransformation after administration to generate the API in situ. Although sharing this general characteristic, prodrugs encompass a wide range of different chemical structures, therapeutic indications and properties. Here we provide the first holistic analysis of the current landscape of approved prodrugs using cheminformatics and data science approaches to reveal trends in prodrug development. We highlight rationales that underlie prodrug design, their indications, mechanisms of API release, the chemistry of promoieties added to APIs to form prodrugs and the market impact of prodrugs. On the basis of this analysis, we discuss strengths and limitations of current prodrug approaches and suggest areas for future development.The development of prodrugs — derivatives of active pharmaceutical ingredients (APIs) with little or no biological activity themselves that are converted into the API after administration — can address issues with properties of the API such as poor bioavailability. This article provides a holistic analysis of approved prodrugs and discusses trends in prodrug design, their indications, mechanisms of API release and the chemistry of promoieties added to APIs to form prodrugs.

The conjugation of therapeutic agents to polymer carriers, such as polyethylene glycol (PEG), can control drug delivery, enhance solubilization, increase efficacy and improve pharmacokinetics. Here, Grinstaff, Colson and Ekladious discuss recent advances in the preclinical and clinical development of different classes of polymer–drug conjugates and highlight current challenges and future directions.

Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR ( N -methyl- d -aspartate receptor) antagonist ( R , S )-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of ( R , S )-ketamine to (2 S ,6 S ;2 R ,6 R )-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2 R ,6 R )-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2 R ,6 R )-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of ( R , S )-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants. The metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and the (2R,6R)-HNK enantiomer lacks ketamine-related side effects but exerts rapid and sustained antidepressant actions in mice; these antidepressant effects are independent of NMDAR inhibition but require AMPAR activity. Antidepressant action of a ketamine metabolite The NMDAR antagonist ketamine has rapid and sustained antidepressant effects; this has prompted a search for alternative NMDAR antagonists that have the same antidepressant properties but lack the undesirable side effects of ketamine. Todd Gould and colleagues now show that the metabolism of ( R , S )-ketamine to (2 S ,6 S ;2 R ,6 R )-hydroxynorketamine (HNK) is essential for its antidepressant activity, and that the (2 R ,6 R )-HNK enantiomer exerts rapid and sustained antidepressant actions in mice. These effects are NMDAR-independent but require AMPAR activation. Importantly, (2 R ,6 R )-HNK lacks the side effects associated with ketamine. These findings suggest new options for the development of novel rapid-acting antidepressants.

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment. The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.

Cannabis is a complex mixture of hundreds of bioactive molecules. This provides the potential for pharmacological interactions between cannabis constituents, a phenomenon referred to as “the entourage effect” by the medicinal cannabis community. We hypothesize that pharmacokinetic interactions between cannabis constituents could substantially alter systemic cannabinoid concentrations. To address this hypothesis we compared pharmacokinetic parameters of cannabinoids administered orally in a cannabis extract to those administered as individual cannabinoids at equivalent doses in mice. Astonishingly, plasma cannabidiolic acid (CBDA) concentrations were 14-times higher following administration in the cannabis extract than when administered as a single molecule. In vitro transwell assays identified CBDA as a substrate of the drug efflux transporter breast cancer resistance protein (BCRP), and that cannabigerol and Δ 9 -tetrahydrocannabinol inhibited the BCRP-mediated transport of CBDA. Such a cannabinoid-cannabinoid interaction at BCRP transporters located in the intestine would inhibit efflux of CBDA, thus resulting in increased plasma concentrations. Our results suggest that cannabis extracts provide a natural vehicle to substantially enhance plasma CBDA concentrations. Moreover, CBDA might have a more significant contribution to the pharmacological effects of orally administered cannabis extracts than previously thought.

The therapeutic index of drug candidates — a quantitative relationship between their safety and efficacy, such as the ratio of the highest exposure to a drug that does not cause toxicity to the exposure that has the desired pharmacological effects — is widely used to aid decision-making in drug discovery and development. Muller and Milton discuss key issues in the calculation and interpretation of therapeutic indices at different stages of the process. A key part of drug discovery and development is the characterization and optimization of the safety and efficacy of drug candidates to identify those that have an appropriately balanced safety–efficacy profile for a given indication. The therapeutic index (TI) — which is typically considered as the ratio of the highest exposure to the drug that results in no toxicity to the exposure that produces the desired efficacy — is an important parameter in efforts to achieve this balance. Various types of safety and efficacy data are generated in vitro and in vivo (in animals and in humans), and these data can be used to predict the clinical TI of a drug candidate at an early stage. However, approaches to systematically and quantitatively compare these types of data and to apply this knowledge more effectively are needed. This article critically discusses the various aspects of TI determination and interpretation in drug development for both small molecule drugs and biotherapeutics.

Key Points Kynurenic acid has potentially neuroprotective actions, such as antagonism at NMDA ( N -methyl- D -aspartate) receptors, inhibition of glutamate release and free radical scavenging. Pharmacological manipulations to harness the beneficial effects of this blood–brain barrier-impermeable agent include increasing the availability of its precursor L -kynurenine, modulation of the kynurenine pathway enzymes towards the synthesis of kynurenic acid, as well as the systemic administration of kynurenic acid analogues that have improved pharmacokinetic characteristics. Most of the kynurenines are neuroactive; they have important roles in the functioning of glutamate receptors and in free radical production. NMDA receptor-mediated excitotoxicity and excessive free radical production are involved in neurodegenerative diseases such as Huntington's disease. The kynurenine pathway is altered in Huntington's disease to favour the production of toxic metabolites, and the possible therapeutic potential of its pharmacological modulation is currently under experimental investigation. Glutamatergic neurotransmission is essential for the spinal and trigeminal processing of pain. Kynurenic acid has several antiglutamatergic properties. Therefore, the elevation of kynurenic acid levels could have therapeutic value in pain syndromes, including migraine. In this disorder, increases in kynurenic acid levels could suppress trigeminal and higher-order nociceptive neurons, modulate migraine generator nuclei in the brainstem and inhibit cortical spreading depression. The activation of indoleamine 2,3-dioxygenase triggers a complex immunomodulatory response, which is involved in the mediation of physiological and pathological immune tolerance. The immunosuppressive effect of this enzyme is attributable to tryptophan depletion and the actions of downstream kynurenine metabolites. There is evidence to indicate that indoleamine 2,3-dioxygenase is activated in several inflammatory and autoimmune conditions, most probably serving as a self-protecting mechanism. Experimental and indirect evidence suggests that the kynurenine pathway is overactivated in multiple sclerosis. As most of the immunotolerogenic metabolites of the kynurenine pathway exert neurotoxic and/or oligotoxic properties, the influence of this phenomenon on the pathogenesis and progression of multiple sclerosis necessitates further investigation. In experimental models of multiple sclerosis, the activation of indoleamine 2,3-dioxygenase has shown beneficial effects; indeed, this mechanism may underlie the therapeutic potential of interferon-β in multiple sclerosis. Structurally similar synthetic derivatives of kynurenines have shown disease-modifying effects in recent clinical trials. The complex anti-inflammatory and neuroprotective properties of kynurenic acid and its analogues suggest that experimental screening of such compounds is warranted. Most metabolites of the kynurenine pathway — which metabolizes tryptophan — are neuroactive. This Review describes the role of the kynurenine pathway in the pathology of Huntington's disease, migraine and multiple sclerosis, and highlights the most promising compounds that could be of therapeutic value. Various pathologies of the central nervous system (CNS) are accompanied by alterations in tryptophan metabolism. The main metabolic route of tryptophan degradation is the kynurenine pathway; its metabolites are responsible for a broad spectrum of effects, including the endogenous regulation of neuronal excitability and the initiation of immune tolerance. This Review highlights the involvement of the kynurenine system in the pathology of neurodegenerative disorders, pain syndromes and autoimmune diseases through a detailed discussion of its potential implications in Huntington's disease, migraine and multiple sclerosis. The most effective preclinical drug candidates are discussed and attention is paid to currently under-investigated roles of the kynurenine pathway in the CNS, where modulation of kynurenine metabolism might be of therapeutic value.

Key Points MicroRNAs (miRNAs) are short, single-stranded RNAs that suppress protein expression of often several related components of complex intracellular networks, making them very potent regulators. The functions of miRNAs are heightened under conditions of pathophysiological stress and disease, making them attractive candidates for therapeutic manipulation. Many gain- and loss-of-function studies have shown that miRNAs have prominent roles during many different diseases, including cardiovascular disorders. Several antimiR (miRNA inhibitor) chemistries exist that can induce potent and sustained inhibition of specific miRNAs. This Review provides an overview of the pharmacokinetic and pharmacodynamic properties of the different antimiR therapeutics and discusses some of their differences in comparison with more classical drugs. We present some recent representative examples of the therapeutic effects of antimiRs in the cardiovascular system, including in cardiac remodelling, metabolism, fibrosis, apoptosis, vascular diseases, inflammation and hypertension. Last, we consider some possible future directions and present some of the challenges and questions that remain in the path towards the development of miRNA-based therapeutics in general. MicroRNAs (miRNAs) are involved in the regulation of gene expression and have been implicated in the pathology of several diseases. Here, van Rooij and Olson discuss the chemistry of current miRNA inhibitors and evaluate miRNAs as potential therapeutic targets for cardiovascular disorders. In recent years, prominent roles for microRNAs (miRNAs) have been uncovered in several cardiovascular disorders. The ability to therapeutically manipulate miRNA expression and function through systemic or local delivery of miRNA inhibitors, referred to as antimiRs, has triggered enthusiasm for miRNAs as novel therapeutic targets. Here, we focus on the pharmacokinetic and pharmacodynamic properties of current antimiR designs and their relevance to cardiovascular indications, and evaluate the opportunities and obstacles associated with this new therapeutic modality.

Key Points Membrane transporters are increasingly being recognized as important determinants of pharmacokinetics and have been found to play a role in the absorption and disposition of many drugs. In this report, the findings of the International Transporter Consortium (ITC), a group of individuals from academia, industry and regulatory agencies with expertise in membrane transporters, are presented. The goals of the ITC were to identify key transporters with a role in drug absorption and disposition; evaluate methodologies for characterization of drug transporter interactions; and develop criteria to inform the conduct of clinical drug–drug interaction (DDI) studies focused on transporters, which could be presented in the form of decision trees. The key transporters, P-glycoprotein (P-gp, ABCB1); breast cancer resistance protein (BCRP); organic anion transporters (OAT1 and OAT3); organic cation transporter (OCT2); and organic anion transporting polypeptides (OATP1B1 and OATP1B3), described in this report were selected based on evidence in the literature demonstrating that the transporters play a role in governing drug absorption and disposition and in mediating clinical DDIs. For each of the key transporters, substrate and inhibitors and methodologies for evaluating its function are described. The clinical significance of each transporter is discussed. An overview of the methods for studying drug interactions with transporters is presented including cell- and membrane-based systems, intact organs and in vivo models. A section on computational modelling algorithms using information from crystal structures and ligands is included to inform readers about the use of in silico methods to gain information about transporter–substrate interactions. A detailed discussion and suggested decision trees related to studying membrane transporters in drug development are described. The focus of the decision trees is on informing clinical DDI studies. Membrane transporters play an important part in determining the pharmacokinetics of many drugs. Here, the International Transporter Consortium discusses key transporters with a role in drug absorption and disposition, and provides guidance for clinical drug interaction studies. Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

Background Promising cancer treatments, such as DDR inhibitors, are often challenged by the heterogeneity of responses in clinical trials. The present work aimed to build a computational framework to address those challenges. Methods A semi-mechanistic pharmacokinetic-pharmacodynamic model of tumour growth inhibition was developed to investigate the efficacy of PARP and ATR inhibitors as monotherapies, and in combination. Key features of the DNA damage response were incorporated into the model to allow the emergence of synthetic lethality, including redundant DNA repair pathways that may be impaired due to genetic mutations, and due to PARP and ATR inhibition. Model parameters were calibrated using preclinical in vivo data for PARP inhibitors rucaparib and talazoparib and the ATR inhibitor gartisertib. Results The model successfully captured the monotherapy efficacies of rucaparib and talazoparib, as well as the combination efficacy with gartisertib. The model was evaluated against multiple tumour xenografts with diverse genetic backgrounds and was able to capture the observed heterogeneity of response profiles. Conclusions By enabling simulation of in vivo tumour growth inhibition with PARP and ATR inhibitors for specific tumour types, the model provides a rational approach to support the optimisation of dosing regimens to stratified populations.