RESUMO
The human orphan G protein-coupled receptor GPR18, activated by Δ9-tetrahydrocannabinol (THC), constitutes a promising drug target in immunology and cancer. However, studies on GPR18 are hampered by the lack of suitable tool compounds. In the present study, potent and selective GPR18 agonists were developed showing low nanomolar potency at human and mouse GPR18, determined in ß-arrestin recruitment assays. Structure-activity relationships were analyzed, and selectivity versus cannabinoid (CB) and CB-like receptors was assessed. Compound 51 (PSB-KK1415, EC50 19.1 nM) was the most potent GPR18 agonist showing at least 25-fold selectivity versus CB receptors. The most selective GPR18 agonist 50 (PSB-KK1445, EC50 45.4 nM) displayed >200-fold selectivity versus both CB receptor subtypes, GPR55, and GPR183. The new GPR18 agonists showed minimal species differences, while THC acted as a weak partial agonist at the mouse receptor. The newly discovered compounds represent the most potent and selective GPR18 agonists reported to date.
Assuntos
Receptores Acoplados a Proteínas G , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Humanos , Animais , Relação Estrutura-Atividade , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Células HEK293 , Receptores de Canabinoides/metabolismo , Dronabinol/farmacologia , Dronabinol/análogos & derivados , Dronabinol/químicaRESUMO
The identification of lead molecules and the exploration of novel pharmacological drug targets are major challenges of medical life sciences today. Genome-wide association studies, multi-omics, and systems pharmacology steadily reveal new protein networks, extending the known and relevant disease-modifying proteome. Unfortunately, the vast majority of the disease-modifying proteome consists of 'orphan targets' of which intrinsic ligands/substrates, (patho)physiological roles, and/or modulators are unknown. Undruggability is a major challenge in drug development today, and medicinal chemistry efforts cannot keep up with hit identification and hit-to-lead optimization studies. New 'thinking-outside-the-box' approaches are necessary to identify structurally novel and functionally distinctive ligands for orphan targets. Here we present a unique dataset that includes critical information on the orphan target ABCA1, from which a novel cheminformatic workflow - computer-aided pattern scoring (C@PS) - for the identification of novel ligands was developed. Providing a hit rate of 95.5% and molecules with high potency and molecular-structural diversity, this dataset represents a suitable template for general deorphanization studies.
Assuntos
Desenho de Fármacos , Descoberta de Drogas , Humanos , Ligantes , Fluxo de TrabalhoRESUMO
Patients with idiopathic pulmonary fibrosis show a strongly upregulated expression of chemokine CXCL14, whose target is still unknown. Screening of CXCL14 in a panel of human G protein-coupled receptors (GPCRs) revealed its potent and selective activation of the orphan MAS-related GPCR X2 (MRGPRX2). This receptor is expressed on mast cells and - like CXCL14 - upregulated in bronchial inflammation. CXCL14 induces robust activation of MRGPRX2 and its putative mouse ortholog MRGPRB2 in G protein-dependent and ß-arrestin recruitment assays that is blocked by a selective MRGPRX2/B2 antagonist. Truncation combined with mutagenesis and computational studies identified the pharmacophoric sequence of CXCL14 and its presumed interaction with the receptor. Intriguingly, C-terminal domain sequences of CXCL14 consisting of 4 to 11 amino acids display similar or increased potency and efficacy compared to the full CXCL14 sequence (77 amino acids). These results provide a rational basis for the future development of potential idiopathic pulmonary fibrosis therapies.
Assuntos
Quimiocinas , Fibrose Pulmonar Idiopática , Animais , Humanos , Camundongos , Aminoácidos , Bioensaio , Quimiocinas CXC , Fibrose Pulmonar Idiopática/genética , Proteínas do Tecido Nervoso/genética , Receptores Acoplados a Proteínas G/genética , Receptores de NeuropeptídeosRESUMO
The discovery of both distinctive lead molecules and novel drug targets is a great challenge in drug discovery, which particularly accounts for orphan diseases. Huntington's disease (HD) is an orphan, neurodegenerative disease of which the pathology is well-described. However, its pathophysiological background and molecular mechanisms are poorly understood. To date, only 2 drugs have been approved on the US and European markets, both of which address symptomatic aspects of this disease only. Although several hundreds of agents were described with efficacy against the HD phenotype in in vitro and/or in vivo models, a successful translation into clinical use is rarely achieved. Two major impediments are, first, the lack of awareness and understanding of the interactome-the sum of key proteins, cascades, and mediators-that contributes to HD initiation and progression; and second, the translation of the little gained knowledge into useful model systems. To counteract this lack of data awareness, we manually compiled and curated the entire modulator landscape of successfully evaluated pre-clinical small-molecule HD-targeting agents which are annotated with substructural molecular patterns, physicochemical properties, as well as drug targets, and which were linked to benchmark databases such as PubChem, ChEMBL, or UniProt. Particularly, the annotation with substructural molecular patterns expressed as binary code allowed for the generation of target-specific and -unspecific fingerprints which could be used to determine the (poly)pharmacological profile of molecular-structurally distinct molecules.
RESUMO
The MAS-related Gq protein-coupled receptor X4 (MRGPRX4) is poorly investigated. MRGPRX4 has been proposed to be involved in pain transmission, itch, inflammation, wound healing, and cancer. However, so far only a few moderately potent, nonselective MRGPRX4 agonists have been described, most of which appear to preferably activate the minor receptor variant MRGPRX4-83L but not the main variant 83S. In the present study, we discovered a xanthine derivative bearing a phosphate substituent that activates the main variant of MRGPRX4. Optimization resulted in analogs with high potency and metabolic stability. The best compounds of the present series include 8-(m-methoxyphenethyl)-1-propargylxanthine substituted with a butyl linker in the 3-position containing a terminal phosphonate (30d, PSB-22034, EC50 Ca2+ assay/ß-arrestin assay, 11.2 nM/32.0 nM) and its N7-methyl derivative 31d (PSB-22040, EC50, 19.2/30.0 nM) showing high selectivity versus all other MRGPRX subtypes. They present promising tool compounds for exploring the potential of MRGPRX4 as a future drug target.
Assuntos
Receptores Acoplados a Proteínas G , Xantinas , Humanos , Receptores Acoplados a Proteínas G/metabolismo , PruridoRESUMO
AIDS (acquired immunodeficiency syndrome) is a potentially life-threatening infectious disease caused by human immunodeficiency virus (HIV). To date, thousands of people have lost their lives annually due to HIV infection, and it continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), to date, 30 drugs have been approved by the FDA, primarily targeting reverse transcriptase, integrase, and/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) includes more than one antiretroviral agent targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular/fragment hybridization, bioisosterism, high-throughput screening, covalent-binding, targeting highly hydrophobic channel, targeting dual site, and multi-target-directed ligand to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapies and long-acting regimens of NNRTIs to improve pharmacokinetic profiles and provide sustained therapeutic effects.
Assuntos
Síndrome da Imunodeficiência Adquirida , Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Infecções por HIV/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Zidovudina/uso terapêutico , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/química , Fármacos Anti-HIV/efeitos adversosRESUMO
Orthomyxo- and bunyaviruses steal the 5' cap portion of host RNAs to prime their own transcription in a process called "cap snatching." We report that RNA modification of the cap portion by host 2'-O-ribose methyltransferase 1 (MTr1) is essential for the initiation of influenza A and B virus replication, but not for other cap-snatching viruses. We identified with in silico compound screening and functional analysis a derivative of a natural product from Streptomyces, called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its S-adenosyl-l-methionine binding pocket to restrict influenza virus replication. Mechanistically, TFMT impairs the association of host cap RNAs with the viral polymerase basic protein 2 subunit in human lung explants and in vivo in mice. TFMT acts synergistically with approved anti-influenza drugs.
Assuntos
Alphainfluenzavirus , Antivirais , Betainfluenzavirus , Produtos Biológicos , Inibidores Enzimáticos , Metiltransferases , Capuzes de RNA , Tubercidina , Replicação Viral , Animais , Humanos , Camundongos , Capuzes de RNA/metabolismo , RNA Mensageiro/metabolismo , RNA Viral/biossíntese , Replicação Viral/efeitos dos fármacos , Alphainfluenzavirus/efeitos dos fármacos , Betainfluenzavirus/efeitos dos fármacos , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Tubercidina/análogos & derivados , Tubercidina/farmacologia , Metiltransferases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Streptomyces/química , Simulação por Computador , Células A549RESUMO
Biomolecular condensates are compartmentalized communities of biomolecules, which unlike traditional organelles, are not enclosed by membranes. Condensates play roles in diverse cellular processes, are dysfunctional in many disease states, and are often enriched in classically "undruggable" targets. In this review, we provide an overview for how drugs can modulate condensate structure and function by phenotypically classifying them as dissolvers (dissolve condensates), inducers (induce condensates), localizers (alter localization of the specific condensate community members) or morphers (alter the physiochemical properties). We discuss the growing list of bioactive molecules that function as condensate modifiers (c-mods), including small molecules, oligonucleotides, and peptides. We propose that understanding mechanisms of condensate perturbation of known c-mods will accelerate the discovery of a new class of therapies for difficult-to-treat diseases.
RESUMO
AIMS: P2X receptors are ATP-gated ion channels which play a role in many pathophysiological conditions. They are considered as novel drug targets, particularly in the fields of pain, (neuro) inflammation, and cancer. Due to difficulties in developing drug-like orthosteric ligands that bind to the highly polar ATP binding site, the design of positive and negative allosteric modulators (PAMs and NAMs) is a promising strategy. The P2X4 receptor was proposed as a novel target for neuropathic and inflammatory pain (antagonists), and for the treatment of alcoholism (PAMs). So far, little is known about the allosteric binding site(s) of P2X4 receptors. The aim of this study was to identify the binding site(s) of the macrocyclic natural product ivermectin, the urea derivative BX430, and the antidepressant drug paroxetine that act as allosteric modulators of P2X4 receptors. MATERIAL AND METHODS: We generated chimeric receptors in which extracellular sequences of the human P2X4 receptor were exchanged for corresponding residues of the human P2X2 receptor, complemented by specific single amino acid residue mutants. Chimeric and mutated receptors were stably expressed in 1321N1 astrocytoma cells, and characterized by fluorimetric measurement of ATP-induced Ca2+-influx. In addition, docking studies utilizing a homology model of the human P2X4 receptor were performed. KEY FINDINGS: Our results suggest a common binding site for ivermectin and BX430 in an extracellular receptor domain, while paroxetine might bind to the cation pore. SIGNIFICANCE: The obtained results provide a basis for the development of positive and negative allosteric P2X4 modulators with improved properties and will support future drug development efforts.
Assuntos
Paroxetina , Receptores Purinérgicos P2X4 , Humanos , Receptores Purinérgicos P2X4/metabolismo , Ivermectina , Sítios de Ligação , Dor , Trifosfato de Adenosina/metabolismoRESUMO
MAS-related G protein-coupled receptors (GPCRs) of subfamily X, designated MRGPRX, are primate-specific orphan receptors that belong to the δ-branch of rhodopsin-like, class A GPCRs. Four distinct subtypes exist, MRGPRX1, -2, -3, and -4, MRGPRX2 having the lowest degree of similarity with the others. Due to their expression on sensory neurons and immune cells, and their roles in pain perception and transmission, itch, inflammation, immune defense, pseudo-allergic reactions, wound healing, and possibly cancer, they have recently attracted much attention as novel drug targets. In particular MRGPRX2 was identified as an important mast cell receptor, responsible for anaphylactoid drug reactions and involved in skin and mucosal diseases, e.g. urticaria, atopic dermatitis, rosacea, and allergic rhinitis. A major hurdle has been the lack of animal models for studying these primate-specific receptors. However, recently humanized mice have been created. Moreover, a mouse ortholog of MRGPRX2, MRGPRB2, was identified, both receptors having a certain degree of similarity. MRGPRX1 and -2 can be activated by various peptides and small (partly peptidomimetic) molecules. MRGPRX2 is additionally activated by a very broad range of basic molecules, positively charged at physiologic pH value of 7.4, including many drugs. MRGPRX4 is activated by small acidic molecules including bile acids. For MRGPRX3, no ligands have been reported yet. Antagonists with reasonable potency and selectivity have been described for MRGPRX1, and few antagonists also for MRGPRX2, but not for the other subtypes. The recent elucidation of cryogenic electron microscopy structures of MRGPRX2 and -4 is expected to facilitate and advance drug development for these receptors. Currently, research on MRGPRX is still in its infancy, and exciting discoveries can be awaited. These receptors have great potential as future drug targets.
Assuntos
Anafilaxia , Peptidomiméticos , Anafilaxia/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Humanos , Mastócitos/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Peptídeos/metabolismo , Peptidomiméticos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos , Rodopsina/metabolismoRESUMO
Multitarget datasets that correlate bioactivity landscapes of small-molecules toward different related or unrelated pharmacological targets are crucial for novel drug design and discovery. ATP-binding cassette (ABC) transporters are critical membrane-bound transport proteins that impact drug and metabolite distribution in human disease as well as disease diagnosis and therapy. Molecular-structural patterns are of the highest importance for the drug discovery process as demonstrated by the novel drug discovery tool 'computer-aided pattern analysis' ('C@PA'). Here, we report a multitarget dataset of 1,167 ABC transporter inhibitors analyzed for 604 molecular substructures in a statistical binary pattern distribution scheme. This binary pattern multitarget dataset (ABC_BPMDS) can be utilized for various areas. These areas include the intended design of (i) polypharmacological agents, (ii) highly potent and selective ABC transporter-targeting agents, but also (iii) agents that avoid clearance by the focused ABC transporters [e.g., at the blood-brain barrier (BBB)]. The information provided will not only facilitate novel drug prediction and discovery of ABC transporter-targeting agents, but also drug design in general in terms of pharmacokinetics and pharmacodynamics.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Preparações Farmacêuticas , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Desenho de Fármacos , Descoberta de Drogas , HumanosRESUMO
Alzheimer's disease (AD) is a devastating neurological disorder characterized by the pathological accumulation of macromolecular Aß and tau leading to neuronal death. Drugs approved to treat AD may ameliorate disease symptoms, however, no curative treatment exists. Aß peptides were discovered to be substrates of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters. Activators of these membrane-bound efflux proteins that promote binding and/or translocation of Aß could revolutionize AD medicine. The knowledge about ABC transporter activators is very scarce, however, the few molecules that were reported contain substructural features of multitarget (pan-)ABC transporter inhibitors. A cutting-edge strategy to obtain new drug candidates is to explore and potentially exploit the recently proposed multitarget binding site of pan-ABC transporter inhibitors as anchor point for the development of innovative activators to promote Aß clearance from the brain. Molecular associations between functional bioactivities and physicochemical properties of small-molecules are key to understand these processes. This study provides an analysis of a recently reported unique multitarget dataset for the correlation between multitarget bioactivity and physicochemistry. Six novel pan-ABC transporter inhibitors were validated containing substructural features of ABC transporter activators, which underpins the relevance of the multitarget binding site for the targeted development of novel AD diagnostics and therapeutics.
Assuntos
Doença de Alzheimer , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Transporte Biológico , Encéfalo/metabolismo , Fenômenos Químicos , HumanosRESUMO
The P2X7 receptor has been proposed as a novel drug target for different types of diseases associated with inflammation, including brain diseases, peripheral inflammation, and cancers. Structurally diverse P2X7 receptor antagonists, mainly negative allosteric modulators (NAMs), have been developed in recent years, and several P2X7 receptor antagonists are currently evaluated in clinical trials. The P2X7 receptor requires high micro- to even millimolar ATP concentrations to be activated. Selective agonists for the P2X7 receptor are not available. Positive allosteric modulators (PAMs) have been described, but PAMs with high potency and selectivity are still lacking. This chapter discusses medicinal chemistry approaches toward the development of P2X7 receptor modulators and presents a selection of recommended tool compounds for studying P2X7 receptors in humans and rodents.
Assuntos
Encefalopatias , Receptores Purinérgicos P2X7 , Química Farmacêutica , Humanos , Inflamação , Antagonistas do Receptor Purinérgico P2X/farmacologiaRESUMO
This review provides an overview of organic compounds detected in non-avian dinosaur fossils to date. This was enabled by the development of sensitive analytical techniques. Non-destructive methods and procedures restricted to the sample surface, e.g., light and electron microscopy, infrared (IR) and Raman spectroscopy, as well as more invasive approaches including liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), time-of-flight secondary ion mass spectrometry, and immunological methods were employed. Organic compounds detected in samples of dinosaur fossils include pigments (heme, biliverdin, protoporphyrin IX, melanin), and proteins, such as collagens and keratins. The origin and nature of the observed protein signals is, however, in some cases, controversially discussed. Molecular taphonomy approaches can support the development of suitable analytical methods to confirm reported findings and to identify further organic compounds in dinosaur and other fossils in the future. The chemical properties of the various organic compounds detected in dinosaurs, and the techniques utilized for the identification and analysis of each of the compounds will be discussed.
RESUMO
In the tumor microenvironment, cancer cells experience hypoxia resulting in the accumulation of misfolded/unfolded proteins largely in the endoplasmic reticulum (ER). Consequently, ER proteotoxicity elicits unfolded protein response (UPR) as an adaptive mechanism to resolve ER stress. In addition to canonical UPR, proteotoxicity also stimulates the selective, autophagy-dependent, removal of discrete ER domains loaded with misfolded proteins to further alleviate ER stress. These mechanisms can favor cancer cell growth, metastasis, and long-term survival. Our investigations reveal that during hypoxia-induced ER stress, the ER-phagy receptor FAM134B targets damaged portions of ER into autophagosomes to restore ER homeostasis in cancer cells. Loss of FAM134B in breast cancer cells results in increased ER stress and reduced cell proliferation. Mechanistically, upon sensing hypoxia-induced proteotoxic stress, the ER chaperone BiP forms a complex with FAM134B and promotes ER-phagy. To prove the translational implication of our mechanistic findings, we identified vitexin as a pharmacological agent that disrupts FAM134B-BiP complex, inhibits ER-phagy, and potently suppresses breast cancer progression in vivo.
Assuntos
Autofagia , Neoplasias da Mama , Autofagia/fisiologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Humanos , Hipóxia/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microambiente TumoralRESUMO
For emerging and re-emerging epidemic infections, researchers face challenges to develop broad-spectrum antivirals as well as reducing development time and costs, and drug resistance. Drug repurposing is a reliable strategy for rapidly discovering potent new antiviral agents, reducing the need for clinical trials. In this review, we outline antiviral drug candidates identified using the drug repurposing approach, with their potential modes of action and biological responses against various epidemic viral infectious diseases.
Assuntos
Epidemias , Vírus , Antivirais/farmacologia , Antivirais/uso terapêutico , Reposicionamento de MedicamentosRESUMO
The human ATP- and UTP-activated P2Y2 receptor (P2Y2R) is a Gq protein-coupled receptor involved in several pathophysiological conditions including acute and chronic inflammation, cancer, and pain. Despite its potential as a novel drug target, only few P2Y2R antagonists have been developed so far, all of which suffer from severe drawbacks. These include (i) high polarity due to one or several negative charges resulting in low oral bioavailability, (ii) metabolic instability and generally poor pharmacokinetic properties, and/or (iii) lack of selectivity, which limits their utility for in vitro and in vivo studies aimed at target validation. In search of new druglike scaffolds for P2Y2R antagonists, we employed a structure-based virtual high-throughput screening approach utilizing the complex of a P2Y2R homology model with one of the most potent and selective orthosteric antagonists described so far, AR-C118925 (10). After virtual screening of 3.2 million molecules, 58 compounds were purchased and pharmacologically evaluated. Several novel antagonist scaffolds were discovered, and their binding modes at the human P2Y2R were analyzed by molecular docking studies. The investigated antagonists likely share a similar binding mode with 10 which includes accommodation of bulky, lipophilic groups in the putative orthosteric binding site of the P2Y2R. The discovered scaffolds and the elucidated structure-activity relationships provide a basis for the development of future drug candidates for the P2Y2R which have great potential as novel drugs.
Assuntos
Ensaios de Triagem em Larga Escala , Antagonistas do Receptor Purinérgico P2Y , Transdução de Sinais , Sítios de Ligação , Humanos , Simulação de Acoplamento Molecular , Antagonistas do Receptor Purinérgico P2Y/química , Receptores Acoplados a Proteínas GRESUMO
MOTIVATION: Multitargeting features of small molecules have been of increasing interest in recent years. Polypharmacological drugs that address several therapeutic targets may provide greater therapeutic benefits for patients. Furthermore, multitarget compounds can be used to address proteins of the same (or similar) protein families for their exploration as potential pharmacological targets. In addition, the knowledge of multitargeting features is of major importance in the drug selection process; particularly in ultra-large virtual screening procedures to gain high-quality compound collections. However, large-scale multitarget modulator landscapes are almost non-existent. RESULTS: We implemented a specific feature-driven computer-aided pattern analysis (C@PA) to extract molecular-structural features of inhibitors of the model protein family of ATP-binding cassette (ABC) transporters. New molecular-structural features have been identified that successfully expanded the known multitarget modulator landscape of pan-ABC transporter inhibitors. The prediction capability was biologically confirmed by the successful discovery of pan-ABC transporter inhibitors with a distinct inhibitory activity profile. AVAILABILITY AND IMPLEMENTATION: The multitarget dataset is available on the PANABC web page (http://www.panabc.info) and its use is free of charge. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Humanos , Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/metabolismoRESUMO
The antithrombotic prodrugs ticlopidine and clopidogrel are thienotetrahydro-pyridine derivatives that are metabolized in the liver to produce thiols that irreversibly block adenosine diphosphate (ADP)-activated P2Y12 receptors on thrombocytes. In their native, nonmetabolized form, both drugs were reported to act as inhibitors of ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39). CD39 catalyzes the extracellular hydrolysis of nucleoside tri- and diphosphates, mainly adenosine 5'-triphosphate (ATP) and ADP, yielding adenosine monophosphate, which is further hydrolyzed by ecto-5'-nucleotidase (CD73) to produce adenosine. While ATP has proinflammatory effects, adenosine is a potent anti-inflammatory, immunosuppressive agent. Inhibitors of CD39 and CD73 have potential as novel checkpoint inhibitors for the immunotherapy of cancer and infection. In the present study, we investigated 2-substituted thienotetrahydropyridine derivatives, structurally related to ticlopidine, as CD39 inhibitors. Due to their substituent on the 2-position, they will not be metabolically transformed into reactive thiols and can, therefore, be expected to be devoid of P2Y12 receptor-antagonistic activity in vivo. Several of the investigated 2-substituted thienotetrahydropyridine derivatives showed concentration-dependent inhibition of CD39. The most potent derivative, 32, showed similar CD39-inhibitory potency to ticlopidine, both acting as allosteric inhibitors. Compound 32 showed an improved selectivity profile: While ticlopidine blocked several NTPDase isoenzymes, 32 was characterized as a novel dual inhibitor of CD39 and CD73.
Assuntos
5'-Nucleotidase/antagonistas & inibidores , Apirase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Tienopiridinas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Proteínas Ligadas por GPI/antagonistas & inibidores , Humanos , Relação Estrutura-Atividade , Tienopiridinas/síntese química , Tienopiridinas/química , Ticlopidina/farmacologiaRESUMO
This review article presents a collection of tool compounds that selectively block and are recommended for studying P2Y and P2X receptor subtypes, investigating their roles in physiology and validating them as future drug targets. Moreover, drug candidates and approved drugs for P2 receptors will be discussed.