Adv. Pharmacol. [JOURNAL]
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200 papers
Anti-fibrotics in inflammatory bowel diseases: Challenges and successes.
Chauhan G, Massey WJ, Veisman I … +1 more , Rieder F
Adv Pharmacol · 2024 · PMID 39521606 · Publisher ↗
Stricture formation leading to obstruction in Crohn's disease (CD) remains one of the largest unmet needs in the field of inflammatory bowel diseases (IBD). Despite this need no selective anti-stricture drug has been app...
Stricture formation leading to obstruction in Crohn's disease (CD) remains one of the largest unmet needs in the field of inflammatory bowel diseases (IBD). Despite this need no selective anti-stricture drug has been approved for use in CD patients. This contrasts with other fibrotic diseases, such as in the lung, liver or kidney, where multiple drug development programs crossed the starting line and two anti-fibrotics are now being approved for pulmonary fibrosis. Strictures are composed of a mix of inflammation, excessive deposition of extracellular matrix (ECM) and smooth muscle hyperplasia, likely all ultimately being responsible for the luminal narrowing driving patient symptoms. Our understanding of the pathogenesis of stricturing CD has evolved and indicates a multifactorial process involving immune and non-immune cells and their soluble mediators. This understanding has rendered target pathways for anti-stricture drug development. Significant progress was made in creating consensus definitions and tools to enable clinical trials with two clinical development programs having been conceived to date. In this chapter, we discuss stricture pathogenesis with a focus on the pathways being tested in clinical trials, and clinical trial endpoints developed for this indication.
The potential of targeting TREM-1 in IBD.
Vinolo E, Maillefer M, Jolly L … +4 more , Colné N, Meiffren G, Carrasco K, Derive M
Adv Pharmacol · 2024 · PMID 39521605 · Publisher ↗
Innate immune dysfunction is a hallmark of the pathogenesis of Inflammatory Bowel Disease, both in Crohn's disease and ulcerative colitis. Despite considerable efforts in research to better understand the pathophysiology...
Innate immune dysfunction is a hallmark of the pathogenesis of Inflammatory Bowel Disease, both in Crohn's disease and ulcerative colitis. Despite considerable efforts in research to better understand the pathophysiology of IBD and for the development of new therapeutic modalities for IBD patients, there is no therapy specifically targeting the dysregulations of the innate immune response available today in that field. TREM-1 is exclusively expressed by innate immune cells and is an immune amplifier. Its engagement following the primary activation of Pattern Recognition Receptors, including Toll-Like Receptors, triggers the development of a dysregulated and sustained innate immune response, promoting the perpetuation of the inflammatory response in the mucosa of IBD patients, microscopic mucosal tissue alterations, impaired autophagy, impaired epithelial barrier integrity and function, ulcerations, and mucosal damages. In patients, TREM-1 activation is associated with the active status of the disease as well as with severity. Blocking TREM-1 in experimental colitis attenuates the dysregulated innate immune response leading to improved clinical signs. Anti-TREM-1 approaches have the potential of controlling the pathogenic dysregulation of the immune response in IBD by targeting an upstream amplification loop of the activation of innate immunity.
TL1A: A model for a precision medicine approach in the treatment of Crohn's disease and ulcerative colitis.
Bilsborough JM, Targan SR
Adv Pharmacol · 2024 · PMID 39521604 · Publisher ↗
Inflammatory bowel disease (IBD) is a collective term for chronic inflammatory diseases of the intestinal tract. The term IBD encompasses two main forms, Crohn's disease (CD) and Ulcerative colitis (UC). CD is characteri...
Inflammatory bowel disease (IBD) is a collective term for chronic inflammatory diseases of the intestinal tract. The term IBD encompasses two main forms, Crohn's disease (CD) and Ulcerative colitis (UC). CD is characterized by inflammation throughout the length of the gut, especially the ileum and colon, and is often complicated with fistulae and/or intestinal strictures. Ulcerative colitis (UC) is inflammatory disease restricted to the colon and rectum. In practice however, IBD is a heterogenous disease with CD and UC representing the extremes of a continuum of diseases with varied clinical presentation, including disease location, severity, and manifestation of extraintestinal diseases. This disease heterogeneity poses a challenge to successful and efficacious therapeutic treatment as the etiology driving disease in individual patients is unknown and likely to be multifactorial, including genetic predisposition, environmental factors such as the microbiota, as well as social behaviors such as smoking and diet. Precision medicine provides a strategy to account for disease heterogeneity and diverse etiology to select for patients most likely to respond to a given therapeutic. In this chapter we present an example of the development of a novel antibody therapeutic, Tulisokibart, as a model for a Precision Medicine approach to the successful treatment of patients with IBD.
Targeting glutamate carboxypeptidase II in IBD.
Peters DE
Adv Pharmacol · 2024 · PMID 39521603 · Full text
Over the past decade, the zinc metalloenzyme glutamate carboxypeptidase (GCPII) has emerged as a novel therapeutic target for IBD. This enzyme is minimally expressed in healthy ileum or colon, but is profoundly upregulat...
Over the past decade, the zinc metalloenzyme glutamate carboxypeptidase (GCPII) has emerged as a novel therapeutic target for IBD. This enzyme is minimally expressed in healthy ileum or colon, but is profoundly upregulated in multiple IBD subtypes including: adult and pediatric Crohn's disease (CD), adult and pediatric ulcerative colitis (UC), and UC pouchitis. Encouragingly, small molecule GCPII inhibitors display promising efficacy in chemical and genetic preclinical colitis models. In this chapter we will: (1) review GCPII biology, (2) present the data confirming its upregulation in IBD patients at gene and protein levels, (3) discuss foundational pre-clinical studies that established the anti-colitis efficacy of small molecule GCPII inhibitors, and (4) introduce the rationale and development of a novel class of GCPII inhibitors, including lead compound (S)-IBD3540, which hold therapeutic promise for IBD.
Dectin-1 as a therapeutic target for inflammatory bowel disease.
Li Y, Huang M, Cardinale S … +4 more , Su Y, Peters DE, Slusher BS, Zhu X
Adv Pharmacol · 2024 · PMID 39521602 · Full text
Inflammatory bowel disease (IBD) encompasses chronic inflammatory conditions of the distal gastrointestinal tract, including Crohn's disease and ulcerative colitis. This chapter explores the potential of Dendritic cell-a...
Inflammatory bowel disease (IBD) encompasses chronic inflammatory conditions of the distal gastrointestinal tract, including Crohn's disease and ulcerative colitis. This chapter explores the potential of Dendritic cell-associated C-type lectin-1 (Dectin-1), a pattern recognition receptor, as a therapeutic target for IBD. We delve into the multifaceted roles of Dectin-1 in immune response modulation, focusing on its interactions with the gut microbiota and immune system. Key sections include an examination of intestinal dysbiosis and its impact on IBD, highlighting the critical role of fungal dysbiosis and immune responses mediated by Dectin-1. The chapter discusses the dual functions of Dectin-1 in maintaining gut homeostasis and its contribution to disease pathogenesis through interactions with the gut's fungal community. Furthermore, the genetic and molecular mechanisms underpinning Dectin-1's role in IBD susceptibility are explored, alongside its signaling pathways and their effects on immune modulation. We also present therapeutic strategies targeting Dectin-1, including innovative drug delivery systems that leverage its natural binding affinity for β-glucans, enhancing targeted delivery to inflamed tissues. The chapter underscores the potential of dietary modulation of Dectin-1 pathways to restore gut microbiota balance and suggests future research directions to fully exploit Dectin-1's therapeutic potential in managing IBD. By elucidating the complex interplay between Dectin-1 and the gut microbiota, this chapter provides insights into novel therapeutic approaches aimed at mitigating IBD symptoms and improving patient outcomes.
BRD4 as an emerging epigenetic therapeutic target for inflammatory bowel disease.
Ma Z, Bolinger AA, Pinchuk IV … +2 more , Tian B, Zhou J
Adv Pharmacol · 2024 · PMID 39521601 · Publisher ↗
Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder, mainly comprising two subtypes: ulcerative colitis (UC) and Crohn's disease (CD). IBD, featured by recurrent symptoms and significant morbidity, po...
Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder, mainly comprising two subtypes: ulcerative colitis (UC) and Crohn's disease (CD). IBD, featured by recurrent symptoms and significant morbidity, poses a significant threat to global health and has an adverse impact on quality of life. Currently, there is no curative therapy for IBD, and the available medications are only for managing the disease condition, likely owing to the insufficient understanding of the underlying pathophysiology processes involved in IBD, and the lack of safe and effective medicines. Thus, novel targeted therapies for IBD are urgently needed for better efficacy with an improved adverse event profile. As the most extensively studied member of bromodomain and extra terminal domain (BET) family proteins, bromodomain-containing protein 4 (BRD4) is emerging as a promising epigenetic therapeutic target for IBD. Pharmacological inhibition of BRD4 with selective small molecule inhibitors shows potent anti-inflammatory effects in both in vitro and different IBD mouse models. Herein, we summarize current knowledge in understanding the role of BRD4 in the pathogenesis and development of IBD, and the clinical landscape of developing BET/BRD4 inhibitors and emerging BRD4-targeted degraders as promising therapeutical alternatives. Challenges and opportunities, as well as future directions in drug discovery by targeting BRD4 are also briefly discussed.
The discovery and development of the sphingosine 1-phosphate receptor modulator ozanimod in ulcerative colitis.
Rosen H, Roberts E
Adv Pharmacol · 2024 · PMID 39521600 · Publisher ↗
Sphingosine-1 phosphate (S1P) modulators have received recent FDA-approval for the treatment of moderate-to-severe ulcerative colitis, including agents ozanimod, approved in 2021, and etrasimod, approved in 2023. These o...
Sphingosine-1 phosphate (S1P) modulators have received recent FDA-approval for the treatment of moderate-to-severe ulcerative colitis, including agents ozanimod, approved in 2021, and etrasimod, approved in 2023. These oral drugs are uniquely efficacious in UC as they have multimodal mechanisms contributing to their beneficial immunomodulatory effects, while preserving host response to pathogens and attenuating toxicities observed with less specific agents. In this review, the discovery and development of the first approved S1P modulator, ozanimod, is described in detail: from design of initial screens to discover unique binding agents, to extensive chemical modifications to improve pharmacokinetic and safety profiles, and through preclinical and clinical studies validating mechanism and establishing safety and efficacy. Ultimately, this review will not only inform the reader of the unique path to development of a clinical S1P modulator for UC, but will also highlight advances made and gaps remaining to individualize therapeutic approaches for inflammatory bowel disease.
Current and emerging therapeutic strategies for perianal fistula in Crohn's disease patients.
Ding K, Kong J, Li L … +3 more , Selaru FM, Parian A, Mao HQ
Adv Pharmacol · 2024 · PMID 39521599 · Full text
The long-term remission rates achieved with current treatment options for Crohn's disease with perianal fistula (CD-PAF)-including antibiotics, biologics, immunomodulators, and Janus kinase inhibitors, often combined wit...
The long-term remission rates achieved with current treatment options for Crohn's disease with perianal fistula (CD-PAF)-including antibiotics, biologics, immunomodulators, and Janus kinase inhibitors, often combined with advanced surgical interventions-remain unsatisfactory. This chapter explores several innovative biomaterials-based solutions, such as plugs, adhesives, fillers, and stem cell-based therapies. The key approaches and treatment outcomes of these advanced therapies are examined, focusing on their ability to modulate the immune response, promote tissue healing, and improve patient outcomes. Additionally, the chapter discusses future directions, including the optimization of biomaterial designs, enhancement of delivery and retention of regenerative therapies, and a deeper understanding of the underlying mechanisms of healing.
AXL: A novel therapeutic target in IBD.
Saeedi BJ, Carr HE, Higgins PDR … +1 more , Steiner CA
Adv Pharmacol · 2024 · PMID 39521598 · Publisher ↗
Inflammatory bowel diseases (IBD) and their sequela (colitis-associate carcinoma and fibrostenotic complications) remain a significant clinical challenge and novel therapeutic targets are desperately needed. AXL, a recep...
Inflammatory bowel diseases (IBD) and their sequela (colitis-associate carcinoma and fibrostenotic complications) remain a significant clinical challenge and novel therapeutic targets are desperately needed. AXL, a receptor tyrosine kinase, has been implicated in myriad cellular functions central to the pathogenesis of IBD. These include facilitating epithelial-to-mesenchymal transition, dampening of Toll-like receptor and natural killer cell mediated immune responses, driving proliferation, and propagating fibrogenic signaling. The vast majority of preclinical research on AXL has focused on its role in cancer. As such, pharmacologic AXL inhibitors are currently in clinical trials, but the indications remain limited to malignancy. In this chapter, we summarize the current preclinical data of AXL in IBD, colitis associated carcinoma, and fibrostenotic disease, and highlight its potential as a novel therapeutic target.
Emerging therapeutics for the management of intestinal fibrosis and strictures.
Neupane YR, Yogananda TM, Rompicharla SVK … +2 more , Selaru FM, Ensign LM
Adv Pharmacol · 2024 · PMID 39521597 · Publisher ↗
Chronic intestinal inflammation in patients with inflammatory bowel disease (IBD) can lead to the development of fibrosis and the formation of strictures. Endoscopic balloon dilation and surgical resection are currently...
Chronic intestinal inflammation in patients with inflammatory bowel disease (IBD) can lead to the development of fibrosis and the formation of strictures. Endoscopic balloon dilation and surgical resection are currently the only available treatments for fibrotic strictures. However, both strategies are associated with potential complications and high rates of stricture recurrence, necessitating additional procedures and/or multiple surgical resections. IBD therapeutic modalities aimed at inflammation, including anti-inflammatory agents, such as corticosteroids, biologics and small molecules, have shown limited efficacy in altering the natural history of strictures, ameliorating fibrosis progression, or preventing recurrences. New and innovative therapeutic approaches targeted at fibrosis are urgently needed. Herein, we provide an overview of emerging therapeutics, including novel drug delivery systems, for the management of intestinal fibrosis and strictures.
The landscape of new therapeutic opportunities for IBD.
Hurtado-Lorenzo A, Swantek JL
Adv Pharmacol · 2024 · PMID 39521596 · Publisher ↗
This chapter presents an overview of the emerging strategies to address the unmet needs in the management of inflammatory bowel diseases (IBD). IBD poses significant challenges, as over half of patients experience diseas...
This chapter presents an overview of the emerging strategies to address the unmet needs in the management of inflammatory bowel diseases (IBD). IBD poses significant challenges, as over half of patients experience disease progression despite interventions, leading to irreversible complications, and a substantial proportion do not respond to existing therapies, such as biologics. To overcome these limitations, we describe a diverse array of novel therapeutic approaches. In the area of immune homeostasis restoration, the focus is on targeting cytokine networks, leukocyte trafficking, novel immune pathways, and cell therapies involving regulatory T cells and mesenchymal stem cells (MSC). Recognizing the critical role of impaired intestinal barrier integrity in IBD, we highlight therapies aimed at restoring barrier function and promoting mucosal healing, such as those targeting cell proliferation, tight junctions, and lipid mediators. Addressing the challenges posed by fibrosis and fistulas, we describe emerging targets for reversing fibrosis like kinase and cytokine inhibitors and nuclear receptor agonists, as well as the potential of MSC for fistulas. The restoration of a healthy gut microbiome, through strategies like fecal microbiota transplantation, rationally defined bacterial consortia, and targeted antimicrobials, is also highlighted. We also describe innovative approaches to gut-targeted drug delivery to enhance efficacy and minimize side effects. Reinforcing these advancements is the critical role of precision medicine, which emphasizes the use of multiomics analysis for the discovery of biomarkers to enable personalized IBD care. Overall, the emerging landscape of therapeutic opportunities for IBD holds great potential to surpass the therapeutic ceiling of current treatments.
Discovery of novel anti-infective agents.
Chatterjee AK
Adv Pharmacol · 2024 · PMID 39034055 · Publisher ↗
Academic and other non-profit institutions have a long-term vision to improve human health where commercial interests can be limited for profit organizations. Medicinal chemistry to these diseases with no commercial bene...
Academic and other non-profit institutions have a long-term vision to improve human health where commercial interests can be limited for profit organizations. Medicinal chemistry to these diseases with no commercial benefit needs is well suited in the academic environment and this chapter outlines some work conducted at Calibr-Skaggs around antibiotic drug development that has led to initiation of multiple clinical trials over the last decade.
IVT-mRNA reprogramming of myeloid cells for cancer immunotherapy.
Jolly KJ, Zhang F
Adv Pharmacol · 2024 · PMID 39034054 · Publisher ↗
In the past decade, in vitro transcribed messenger RNAs (IVT-mRNAs) have emerged as promising therapeutic molecules. The clinical success of COVID-19 mRNA vaccines developed by Pfizer-BioNTech and Moderna, have demonstra...
In the past decade, in vitro transcribed messenger RNAs (IVT-mRNAs) have emerged as promising therapeutic molecules. The clinical success of COVID-19 mRNA vaccines developed by Pfizer-BioNTech and Moderna, have demonstrated that IVT-mRNAs can be safely and successfully used in a clinical setting, and efforts are underway to develop IVT-mRNAs for therapeutic applications. Current applications of mRNA-based therapy have been focused on (1) mRNA vaccines for infectious diseases and cancer treatment; (2) protein replacement therapy; (3) gene editing therapy; and (4) cell-reprogramming therapies. Due to the recent clinical progress of cell-based immunotherapies, the last direction-the use of IVT-mRNAs as a therapeutic approach to program immune cells for the treatment of cancer has received extensive attention from the cancer immunotherapy field. Myeloid cells are important components of our immune system, and they play critical roles in mediating disease progression and regulating immunity against diseases. In this chapter, we discussed the progress of using IVT-mRNAs as a therapeutic approach to program myeloid cells against cancer and other immune-related diseases. Towards this direction, we first reviewed the pharmacology of IVT-mRNAs and the biology of myeloid cells as well as myeloid cell-targeting therapeutics. We then presented a few cases of current IVT-mRNA-based approaches to target and reprogram myeloid cells for disease treatment and discussed the advantages and limitations of these approaches. Finally, we presented our considerations in designing mRNA-based approaches to target myeloid cells for disease treatment.
Targeting proliferating cell nuclear antigen (PCNA) for cancer therapy.
Søgaard CK, Otterlei M
Adv Pharmacol · 2024 · PMID 39034053 · Publisher ↗
Proliferating cell nuclear antigen (PCNA) is an essential scaffold protein in many cellular processes. It is best known for its role as a DNA sliding clamp and processivity factor during DNA replication, which has been e...
Proliferating cell nuclear antigen (PCNA) is an essential scaffold protein in many cellular processes. It is best known for its role as a DNA sliding clamp and processivity factor during DNA replication, which has been extensively reviewed by others. However, the importance of PCNA extends beyond its DNA-associated functions in DNA replication, chromatin remodelling, DNA repair and DNA damage tolerance (DDT), as new non-canonical roles of PCNA in the cytosol have recently been identified. These include roles in the regulation of immune evasion, apoptosis, metabolism, and cellular signalling. The diverse roles of PCNA are largely mediated by its myriad protein interactions, and its centrality to cellular processes makes PCNA a valid therapeutic anticancer target. PCNA is expressed in all cells and plays an essential role in normal cellular homeostasis; therefore, the main challenge in targeting PCNA is to selectively kill cancer cells while avoiding unacceptable toxicity to healthy cells. This chapter focuses on the stress-related roles of PCNA, and how targeting these PCNA roles can be exploited in cancer therapy.
Progress in the development of ERK1/2 inhibitors for treating cancer and other diseases.
Grogan L, Shapiro P
Adv Pharmacol · 2024 · PMID 39034052 · Publisher ↗
The extracellular signal-regulated kinases-1 and 2 (ERK1/2) are ubiquitous regulators of many cellular functions, including proliferation, differentiation, migration, and cell death. ERK1/2 regulate cell functions by pho...
The extracellular signal-regulated kinases-1 and 2 (ERK1/2) are ubiquitous regulators of many cellular functions, including proliferation, differentiation, migration, and cell death. ERK1/2 regulate cell functions by phosphorylating a diverse collection of protein substrates consisting of other kinases, transcription factors, structural proteins, and other regulatory proteins. ERK1/2 regulation of cell functions is tightly regulated through the balance between activating phosphorylation by upstream kinases and inactivating dephosphorylation by phosphatases. Disruption of homeostatic ERK1/2 regulation caused by elevated extracellular signals or mutations in upstream regulatory proteins leads to the constitutive activation of ERK1/2 signaling and uncontrolled cell proliferation observed in many types of cancer. Many inhibitors of upstream kinase regulators of ERK1/2 have been developed and are part of targeted therapeutic options to treat a variety of cancers. However, the efficacy of these drugs in providing sustained patient responses is limited by the development of acquired resistance often involving re-activation of ERK1/2. As such, recent drug discovery efforts have focused on the direct targeting of ERK1/2. Several ATP competitive ERK1/2 inhibitors have been identified and are being tested in cancer clinical trials. One drug, Ulixertinib (BVD-523), has received FDA approval for use in the Expanded Access Program for patients with no other therapeutic options. This review provides an update on ERK1/2 inhibitors in clinical trials, their successes and limitations, and new academic drug discovery efforts to modulate ERK1/2 signaling for treating cancer and other diseases.
Therapeutic resurgence of 6-diazo-5-oxo-l-norleucine (DON) through tissue-targeted prodrugs.
Novotná K, Tenora L, Slusher BS … +1 more , Rais R
Adv Pharmacol · 2024 · PMID 39034051 · Publisher ↗
The recognition that rapidly proliferating cancer cells rely heavily on glutamine for their survival and growth has renewed interest in the development of glutamine antagonists for cancer therapy. Glutamine plays a pivot...
The recognition that rapidly proliferating cancer cells rely heavily on glutamine for their survival and growth has renewed interest in the development of glutamine antagonists for cancer therapy. Glutamine plays a pivotal role as a carbon source for synthesizing lipids and metabolites through the TCA cycle, as well as a nitrogen source for synthesis of amino acid and nucleotides. Numerous studies have explored the significance of glutamine metabolism in cancer, providing a robust rationale for targeting this metabolic pathway in cancer treatment. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) has been explored as an anticancer therapeutic for nearly six decades. Initial investigations revealed remarkable efficacy in preclinical studies and promising outcomes in early clinical trials. However, further advancement of DON was hindered due to dose-limiting gastrointestinal (GI) toxicities as the GI system is highly dependent on glutamine for regulating growth and repair. In an effort to repurpose DON and mitigate gastrointestinal (GI) toxicity concerns, prodrug strategies were utilized. These strategies aimed to enhance the delivery of DON to specific target tissues, such as tumors and the central nervous system (CNS), while sparing DON delivery to normal tissues, particularly the GI tract. When administered at low daily doses, optimized for metabolic inhibition, these prodrugs exhibit remarkable effectiveness without inducing significant toxicity to normal tissues. This approach holds promise for overcoming past challenges associated with DON, offering an avenue for its successful utilization in cancer treatment.
Journey from lab to clinic: Design, preclinical, and clinical development of systemic, targeted dendrimer-N-acetylcysteine (D-NAC) nanomedicines.
Liyanage W, Kale N, Kannan S … +1 more , Kannan RM
Adv Pharmacol · 2024 · PMID 39034050 · Publisher ↗
Drug discovery is challenging task with numerous obstacles in translating drug candidates into clinical products. Dendrimers are highly adaptable nanostructured polymers with significant potential to improve the chances...
Drug discovery is challenging task with numerous obstacles in translating drug candidates into clinical products. Dendrimers are highly adaptable nanostructured polymers with significant potential to improve the chances of clinical success for drugs. Yet, dendrimer-based drug products are still in their infancy. However, Hydroxyl polyamidoamine (PAMAM) dendrimers showed significant promise in drug discovery efforts, owning their remarkable potential to selectively target and deliver drugs specifically to activated microglia and astrocytes at the site of brain injury in several preclinical models. After a decade's worth of academic research and pre-clinical efforts, the hydroxyl PAMAM dendrimer-N-acetyl cysteine conjugate (OP-101) nanomedicine has made a significant advancement in the field of nanomedicine and targeted delivery. The OP-101 conjugate, primarily developed and validated in academic labs, has now entered clinical trials as a potential treatment for hyperinflammation in hospitalized adults with severe COVID-19 through Ashvattha Therapeutics. This chapter, we delve into the journey of the hydroxyl PAMAM dendrimer-N-acetylcysteine (NAC) OP-101 formulation from the laboratory to the clinic. It will specifically focus on the design, synthesis, preclinical, and clinical development of OP-101, highlighting the potential it holds for the future of medicine and the positive Phase 2a results for treating severe COVID-19.
Making new drugs the hard way.
Liotta D
Adv Pharmacol · 2024 · PMID 39034049 · Publisher ↗
A new drug can have its origin in either pharma, biotech or academia. In general, discovery scientists working in pharma and biotech are advantaged over their academic counterparts and the relative advantages and disadva...
A new drug can have its origin in either pharma, biotech or academia. In general, discovery scientists working in pharma and biotech are advantaged over their academic counterparts and the relative advantages and disadvantages associated are discussed in depth. Against all odds, an increasing number of important drugs have had their origins in academia. This article reports three case studies from the Liotta Research Group (LRG), which explores the special circumstances that allowed these drug development campaigns to be successful. The first involves the antiretroviral agent, emtricitabine. In this case efficient synthetic methodology, developed in the LRG, coupled with some key university and commercial sector partnerships, enabled a group of academic collaborators to discover and develop a highly effective HIV reverse transcriptase inhibitor. The second case study involves the discovery and development of the breakthrough hepatitis C drug, sofosbuvir. Based on key input from Professors Schinazi and Liotta at Emory University, scientists at the Emory startup, Pharmasset, identified the nucleoside core of the drug that would become sofosbuvir. Subsequent analysis of its phosphorylation profile by Pharmasset scientists suggested that converting it to its corresponding monophosphate prodrug would circumvent a kinase block and enable it to be an effective hepatitis C polymerase inhibitor. The third case study describes the formation of DRIVE (Drug Innovation Ventures at Emory)/EIDD (Emory Institute for Drug Development), which were created to circumvent unintended impediments for carrying out academic drug discovery and development. Although DRIVE/EIDD is a wholly-owned, not-for-profit subsidiary of Emory University, it contains many attributes that enables it to operate much more nimbly than a typical academic laboratory. With an experienced drug development team and no shareholders to distract them, DRIVE/EIDD was able to focus its attention of the development of drugs to address viral diseases of global concern. In particular, their strategy to identify and develop an antiviral agent active against multiple single-stranded RNA viruses led to molnupiravir, a broadly active, oral drug that received Emergency Use Authorization for the treatment of SARS-CoV-2 infections (i.e., COVID-19).
Structural and functional perspectives on interactions between synthetic cathinones and monoamine transporters.
Nguyen VT, Harris AC, Eltit JM
Adv Pharmacol · 2024 · PMID 38467490 · Full text
Synthetic cathinone derivatives comprise a family of psychoactive compounds structurally related to amphetamine. Over the last decade, clandestine chemists have synthesized a consistent stream of innovative cathinone der...
Synthetic cathinone derivatives comprise a family of psychoactive compounds structurally related to amphetamine. Over the last decade, clandestine chemists have synthesized a consistent stream of innovative cathinone derivatives to outpace governmental regulatory restrictions. Many of these unregulated substances are produced and distributed as designer drugs. Two of the principal chemical scaffolds exploited to expand the synthetic cathinone family are methcathinone and α-pyrrolidinopentiophenone (or α-pyrrolidinovalerophenone, α-PVP). These compounds' main physiological targets are monoamine transporters, where they promote addiction by potentiating dopaminergic neurotransmission. This chapter describes techniques used to study the pharmacodynamic properties of cathinones at monoamine transporters in vitro. Biochemical techniques described include uptake inhibition and release assays in rat brain synaptosomes and in mammalian expression systems. Electrophysiological techniques include current measurements using the voltage clamp technique. We describe a Ca mobilization assay wherein voltage-gated Ca channels function as reporters to study the action of synthetic cathinones at monoamine transporters. We discuss results from systematic structure-activity relationship studies on simple and complex cathinones at monoamine transporters with an emphasis on identifying structural moieties that modulate potency and selectivity at these transporters. Moreover, different profiles of selectivity at monoamine transporters directly predict compounds associated with behavioral and subjective effects within animals and humans. In conclusion, clarification of the structural aspects of compounds which modulate potency and selectivity at monoamine transporters is critical to identify and predict potential addictive drugs. This knowledge may allow prompt allocation of resources toward drugs that represent the greatest threats after drugs are identified by forensic laboratories.
The pharmacology and neurotoxicology of synthetic cathinones.
Angoa-Perez M, Kuhn DM
Adv Pharmacol · 2024 · PMID 38467489 · Publisher ↗
The synthetic cathinones are man-made compounds derived from the naturally occurring drug cathinone, which is found in the khat plant. The drugs in this pharmacological class that will be the focus of this chapter includ...
The synthetic cathinones are man-made compounds derived from the naturally occurring drug cathinone, which is found in the khat plant. The drugs in this pharmacological class that will be the focus of this chapter include mephedrone, MDPV, methcathinone and methylone. These drugs are colloquially known as "bath salts". This misnomer suggests that these drugs are used for health improvement or that they have legitimate medical uses. The synthetic cathinones are dangerous drugs with powerful pharmacological effects that include high abuse potential, hyperthermia and hyperlocomotion. These drugs also share many of the pharmacological effects of the amphetamine class of drugs including methamphetamine, amphetamine and MDMA and therefore have high potential to cause damage to the central nervous system. The synthetic cathinones are frequently taken in combination with other psychoactive drugs such as alcohol, marijuana and the amphetamine-like stimulants, creating a situation where heightened pharmacological and neurotoxicological effects are likely to occur. Despite the structural features shared by the synthetic cathinones and amphetamine-like stimulants, including their actions at monoamine transporters and receptors, the effects of the synthetic cathinones do not always match those of the amphetamines. In particular, the synthetic cathinones are far less neurotoxic than their amphetamine counterparts, they produce a weaker hyperthermia, and they cause less glial activation. This chapter will briefly review the pharmacology and neurotoxicology of selected synthetic cathinones with the aim of delineating key areas of agreement and disagreement in the literature particularly as it relates to neurotoxicological outcomes.
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