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1.
Chem Rev ; 123(23): 13693-13712, 2023 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-37975808

RESUMO

An overview of Parkinson's disease (PD) prevalence, diagnosis, and currently available treatment options is provided. A comprehensive list of different classes of marketed pharmaceutical drug products and the syntheses of various drug substances are summarized based on published literature.


Assuntos
Antiparkinsonianos , Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/epidemiologia , Preparações Farmacêuticas , Antiparkinsonianos/classificação , Prevalência
2.
J Med Chem ; 66(23): 15883-15893, 2023 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-38016916

RESUMO

Early assessment of crystalline thermodynamic solubility continues to be elusive for drug discovery and development despite its critical importance, especially for the ever-increasing fraction of poorly soluble drug candidates. Here we present a detailed evaluation of a physics-based free energy perturbation (FEP+) approach for computing the thermodynamic aqueous solubility. The predictive power of this approach is assessed across diverse chemical spaces, spanning pharmaceutically relevant literature compounds and more complex AbbVie compounds. Our approach achieves predictive (RMSE = 0.86) and differentiating power (R2 = 0.69) and therefore provides notably improved correlations to experimental solubility compared to state-of-the-art machine learning approaches that utilize quantum mechanics-based descriptors. The importance of explicit considerations of crystalline packing in predicting solubility by the FEP+ approach is also highlighted in this study. Finally, we show how computed energetics, including hydration and sublimation free energies, can provide further insights into molecule design to feed the medicinal chemistry DMTA cycle.


Assuntos
Descoberta de Drogas , Água , Solubilidade , Entropia , Termodinâmica , Água/química
3.
Bioorg Med Chem Lett ; 72: 128843, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35688367

RESUMO

Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein (F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF use a dual or triple combination of CFTR correctors and potentiators. In triple therapy, two correctors (C1 and C2) and a potentiator are employed. Herein, we describe the identification and exploration of the SAR of a series of 4-aminopyrrolidine-2-carboxylic acid C2 correctors of CFTR to be used in conjunction with our existing C1 corrector series for the treatment of CF.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Benzodioxóis , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Mutação , Prolina/análogos & derivados , Relação Estrutura-Atividade
4.
Bioorg Med Chem ; 63: 116743, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35436748

RESUMO

The voltage-gated sodium channel Nav1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Nav1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Nav1.7 blockers with oral activity, improved selectivity, good drug-like properties, and safety led to the discovery of 2-substituted quinolines and quinolones as potent small molecule Nav1.7 blockers. The design of these molecules focused on maintaining potency at Nav1.7, improving selectivity over the hERG channel, and overcoming phospholipidosis observed with the initial leads. The structure-activity relationship (SAR) studies leading to the discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) are described herein. ABBV-318 displayed robust in vivo efficacy in both inflammatory and neuropathic rodent models of pain. ABBV-318 also inhibited Nav1.8, another sodium channel isoform that is an active target for the development of new pain treatments.


Assuntos
Dor , Canais de Sódio , Humanos , Dor/tratamento farmacológico , Manejo da Dor , Isoformas de Proteínas , Canais de Sódio/metabolismo , Relação Estrutura-Atividade
5.
ACS Med Chem Lett ; 12(9): 1365-1373, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34531945

RESUMO

The paramount importance of synthetic organic chemistry in the pharmaceutical industry arises from the necessity to physically prepare all designed molecules to obtain key data to feed the design-synthesis-data cycle, with the medicinal chemist at the center of this cycle. Synthesis specialists accelerate the cycle of medicinal chemistry innovation by rapidly identifying and executing impactful synthetic methods and strategies to accomplish project goals, addressing the synthetic accessibility bottleneck that often plagues discovery efforts. At AbbVie, Discovery Synthesis Groups (DSGs) such as Centralized Organic Synthesis (COS) have been deployed as embedded members of medicinal chemistry teams, filling the gap between discovery and process chemistry. COS chemists provide synthetic tools, scaffolds, and lead compounds to fuel the pipeline. Examples of project contributions from neuroscience, cystic fibrosis, and virology illustrate the impact of the DSG approach. In the first ten years of innovative science in pursuit of excellence in synthesis, several advanced drug candidates, including ABBV-2222 (galicaftor) for cystic fibrosis and foslevodopa/foscarbidopa for Parkinson's disease, have emerged with key contributions from COS.

6.
Ann Neurol ; 90(1): 52-61, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33772855

RESUMO

OBJECTIVE: The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication. METHODS: Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study. RESULTS: Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated. INTERPRETATION: Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD. ANN NEUROL 2021;90:52-61.


Assuntos
Antiparkinsonianos/uso terapêutico , Carbidopa/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/administração & dosagem , Carbidopa/administração & dosagem , Combinação de Medicamentos , Humanos , Levodopa/administração & dosagem
7.
J Pharmacol Exp Ther ; 372(1): 107-118, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732698

RESUMO

Cystic fibrosis (CF) is the most common monogenic autosomal recessive disease in Caucasians caused by pathogenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (CFTR). Significant small molecule therapeutic advances over the past two decades have been made to target the defective CFTR protein and enhance its function. To address the most prevalent defect of the defective CFTR protein (i.e., F508del mutation) in CF, two biomolecular activities are required, namely, correctors to increase the amount of properly folded F508delCFTR levels at the cell surface and potentiators to allow the effective opening, i.e., function of the F508delCFTR channel. Combined, these activities enhance chloride ion transport yielding improved hydration of the lung surface and subsequent restoration of mucociliary clearance. To enhance clinical benefits to CF patients, a complementary triple combination therapy consisting of two corrector molecules, type 1 (C1) and type 2, with additive mechanisms along with a potentiator are being investigated in the clinic for maximum restoration of mutated CFTR function. We report the identification and in vitro biologic characterization of ABBV-2222/GLPG2222 (4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid),-a novel, potent, and orally bioavailable C1 corrector developed by AbbVie-Galapagos and currently in clinical trials-which exhibits substantial improvements over the existing C1 correctors. This includes improvements in potency and drug-drug interaction (DDI) compared with 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (VX-809, Lumacaftor) and improvements in potency and efficacy compared with 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide (VX-661, Tezacaftor). ABBV-2222/GLPG2222 exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR with an EC50 value <10 nM. SIGNIFICANCE STATEMENT: To address the most prevalent defect of the defective CFTR protein (i.e., F508del mutation) in cystic fibrosis, AbbVie-Galapagos has developed ABBV-2222/GLPG2222, a novel, potent, and orally bioavailable C1 corrector of this protein. ABBV-2222/GLPG2222, which is currently in clinical trials, exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR and substantial improvements over the existing C1 correctors.


Assuntos
Benzoatos/farmacologia , Benzopiranos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Dobramento de Proteína/efeitos dos fármacos , Animais , Sítios de Ligação , Membrana Celular/metabolismo , Células Cultivadas , Cloretos/metabolismo , Cricetinae , Regulador de Condutância Transmembrana em Fibrose Cística/química , Células HEK293 , Humanos , Moduladores de Transporte de Membrana/farmacologia , Ligação Proteica , Transporte Proteico/efeitos dos fármacos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo
8.
ACS Med Chem Lett ; 10(11): 1543-1548, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31749908

RESUMO

Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the CFTR gene, resulting in insufficient or impaired cystic fibrosis transmembrane conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure-activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.

9.
J Med Chem ; 61(4): 1436-1449, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29251932

RESUMO

Cystic fibrosis (CF) is a multiorgan disease of the lungs, sinuses, pancreas, and gastrointestinal tract that is caused by a dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial anion channel that regulates salt and water balance in the tissues in which it is expressed. To effectively treat the most prevalent patient population (F508del mutation), two biomolecular modulators are required: correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel. Despite approved potentiator and potentiator/corrector combination therapies, there remains a high need to develop more potent and efficacious correctors. Herein, we disclose the discovery of a highly potent series of CFTR correctors and the structure-activity relationship (SAR) studies that guided the discovery of ABBV/GLPG-2222 (22), which is currently in clinical trials in patients harboring the F508del CFTR mutation on at least one allele.


Assuntos
Benzoatos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Descoberta de Drogas , Amidas/síntese química , Animais , Benzoatos/síntese química , Benzoatos/farmacocinética , Cromanos/síntese química , Cães , Humanos , Proteínas Mutantes/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
10.
J Neurophysiol ; 118(2): 904-916, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28468993

RESUMO

TRPV3 is a nonselective cation channel activated by temperatures above 33°C and is reported to be localized in keratinocytes and nervous tissue. To investigate a role for TRPV3 in pain modulation, we conducted a series of in vivo electrophysiological studies on spinal and brain nociceptive neurons. Structurally diverse TRPV3 receptor antagonists reduced responses of spinal wide dynamic range (WDR) neurons to low-intensity mechanical stimulation in neuropathic rats, but only CNS-penetrant antagonists decreased elevated spontaneous firing. Injections of an antagonist into the neuronal receptive field, into the L5 dorsal root ganglion, or intracerebroventricularly (ICV) attenuated the evoked firing, but only ICV injections reduced spontaneous activity. Intraspinal injections did not affect either. Spinal transection blocked the effect on spontaneous but not evoked firing after systemic delivery of a TRPV3 antagonist. Systemic administration of an antagonist to neuropathic rats also impacted the firing of On- and Off-cells in the rostral ventromedial medulla in a manner consistent with dampening nociceptive signaling. An assessment of nonevoked "pain," an EEG-measured pain-induced sleep disturbance induced by hind paw injections of CFA, was also improved with CNS-penetrant TRPV3 antagonists but not by an antagonist with poor CNS penetration. Antagonism of TRPV3 receptors modulates activity of key classes of neurons in the pain pathway in a manner consistent with limiting pathological nociceptive signaling and was mediated by receptors in the periphery and brain. Blockade of TRPV3 receptors is likely an effective means to alleviate mechanical allodynia and nonevoked pain. However, the latter will only be obtained by blocking supraspinal TRPV3 receptors.NEW & NOTEWORTHY Recent studies have linked TRPV3 to pain modulation, and much of this work has focused on its role in the skin-primary afferent interface. In this electrophysiological study, we demonstrate that receptor antagonists modulate evoked signals through peripheral mechanisms but blockade of supraspinal TRPV3 receptors contributes to dampening both evoked and nonevoked "pain" through descending modulation. Thus, the full therapeutic potential of TRPV3 antagonists may only be realized with the ability to access receptors in the brain.


Assuntos
Encéfalo/metabolismo , Gânglios Espinais/metabolismo , Dor Nociceptiva/metabolismo , Nociceptores/metabolismo , Medula Espinal/metabolismo , Canais de Cátion TRPV/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Masculino , Moduladores de Transporte de Membrana/química , Moduladores de Transporte de Membrana/farmacologia , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Dor Nociceptiva/tratamento farmacológico , Nociceptores/efeitos dos fármacos , Ratos Sprague-Dawley , Sono/efeitos dos fármacos , Sono/fisiologia , Medula Espinal/efeitos dos fármacos , Canais de Cátion TRPV/antagonistas & inibidores , Técnicas de Cultura de Tecidos
11.
J Org Chem ; 81(23): 12060-12064, 2016 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-27934457

RESUMO

An efficient asymmetric synthesis of dipyridyl TRPV3 antagonist 1 is reported. The four-step route involves two C-C bond-forming steps, a highly diastereoselective alkene hydration, and asymmetric ketone hydrosilylation in 97% ee.


Assuntos
Canais de Cátion TRPV/antagonistas & inibidores , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Piridinas/química , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo
12.
J Med Chem ; 59(10): 4926-47, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27077528

RESUMO

Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.


Assuntos
Ciclobutanos/síntese química , Ciclobutanos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Cálcio/metabolismo , Ciclobutanos/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Conformação Molecular , Piridinas/química , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo
13.
Temperature (Austin) ; 2(2): 150-1, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27227014

RESUMO

This editorial is about the roles that TRP channels play in heat and cold sensation and body temperature regulation. These roles may be exploited for therapeutic purposes (indeed, drugs targeting TRPV1, TRPA1 and TRPM8 channels are currently undergoing clinical trials for indications that range from pain through chronic cough and overactive bladder to cancer) or, conversely, may limit drug development (for example, several TRPV1 antagonists were withdrawn from clinical trials due to the hyperthermic reaction that they caused). In the future, modulation of thermosensitive TRP channels may ultimately find application in the treatment not only of pain, but also itch, stroke, asthma, and metabolic disorders. Of the multitude of targets involved in temperature sensation and body temperature regulation, why TRP channels? And why now?

14.
Temperature (Austin) ; 2(2): 297-301, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27227030

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) is a multifunctional ion channel playing important roles in a numerous biological processes including the regulation of body temperature. Within distinct and tight chemical space of chromanyl ureas TRPV1 ligands were identified that exhibit distinctive pharmacology and a spectrum of thermoregulatory effects ranging from hypothermia to hyperthermia. The ability to manipulate these effects by subtle structural modifications of chromanyl ureas may serve as a productive approach in TRPV1 drug discovery programs addressing either side effect or desired target profiles of the compounds. Because chromanyl ureas in the TRPV1 context are generally antagonists, we verified observed partial agonist effects of a subset of compounds within that chemotype by comparing the in vitro profile of Compound 3 with known partial agonist 5'-I-RTX.

15.
J Med Chem ; 57(17): 7412-24, 2014 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-25100568

RESUMO

The synthesis and characterization of a series of selective, orally bioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described. Whereas first-generation antagonists that inhibit all modes of TRPV1 activation can elicit hyperthermia, the compounds disclosed herein do not elevate core body temperature in preclinical models and only partially block acid activation of TRPV1. Advancing the SAR of this series led to the eventual identification of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442, 52), an analogue that possesses excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents.


Assuntos
Analgésicos/química , Temperatura Corporal/efeitos dos fármacos , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/química , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Área Sob a Curva , Temperatura Corporal/fisiologia , Cães , Relação Dose-Resposta a Droga , Descoberta de Drogas , Células HEK293 , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Taxa de Depuração Metabólica , Modelos Químicos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/química , Canais de Cátion TRPV/metabolismo , Ureia/análogos & derivados , Ureia/farmacocinética , Ureia/farmacologia
16.
J Neurosci ; 34(13): 4445-52, 2014 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-24671991

RESUMO

The rodent transient receptor potential ankyrin-1 (TRPA1) channel has been hypothesized to serve as a temperature sensor for thermoregulation in the cold. We tested this hypothesis by using deletion of the Trpa1 gene in mice and pharmacological blockade of the TRPA1 channel in rats. In both Trpa1(-/-) and Trpa1(+/+) mice, severe cold exposure (8°C) resulted in decreases of skin and deep body temperatures to ∼8°C and 13°C, respectively, both temperatures being below the reported 17°C threshold temperature for TRPA1 activation. Under these conditions, Trpa1(-/-) mice had the same dynamics of body temperature as Trpa1(+/+) mice and showed no weakness in the tail skin vasoconstriction response or thermogenic response to cold. In rats, the effects of pharmacological blockade were studied by using two chemically unrelated TRPA1 antagonists: the highly potent and selective compound A967079, which had been characterized earlier, and the relatively new compound 43 ((4R)-1,2,3,4-tetrahydro-4-[3-(3-methoxypropoxy)phenyl]-2-thioxo-5H-indeno[1,2-d]pyrimidin-5-one), which we further characterized in the present study and found to be highly potent (IC50 against cold of ∼8 nm) and selective. Intragastric administration of either antagonist at 30 mg/kg before severe (3°C) cold exposure did not affect the thermoregulatory responses (deep body and tail skin temperatures) of rats, even though plasma concentrations of both antagonists well exceeded their IC50 value at the end of the experiment. In the same experimental setup, blocking the melastatin-8 (TRPM8) channel with AMG2850 (30 mg/kg) attenuated cold-defense mechanisms and led to hypothermia. We conclude that TRPA1 channels do not drive autonomic thermoregulatory responses to cold in rodents.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Regulação da Temperatura Corporal/genética , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Sensação Térmica/genética , Animais , Regulação da Temperatura Corporal/efeitos dos fármacos , Células CHO , Temperatura Baixa , Cricetulus , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteínas de Choque Térmico HSP90 , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Transgênicos , Oximas/sangue , Oximas/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Temperatura Cutânea/efeitos dos fármacos , Canais de Cátion TRPM/antagonistas & inibidores , Sensação Térmica/efeitos dos fármacos
17.
Eur J Pharmacol ; 716(1-3): 61-76, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23500195

RESUMO

Preclinical research has recently uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which represent opportunities for pharmacological intervention. Manipulating temperature-sensitive Transient Receptor Potential (TRP) channels (so-called "thermoTRPs") on nociceptive neurons is a particularly attractive strategy in that it targets the beginning of the pain pathway. In the focus of current drug development efforts are the heat-sensitive TRPV1, warm-activated TRPV3, cold-responsive TRPA1, and cool-activated TRPM8 channels. TRPV1 desensitization by topical agonists (e.g. high concentration capsaicin creams and patches) has been in clinical use for decades to alleviate chronic painful conditions like diabetic neuropathy. Currently, site-specific resiniferatoxin (an ultrapotent capsaicin analogue) injections are being evaluated as "molecular scalpels" to achieve permanent analgesia in cancer patients with chronic, intractable pain. In the past few years a number of potent, small molecule TRPV1, TRPV3 and TRPA1 antagonists have been advanced into clinical trials for the treatment of inflammatory, neuropathic and visceral pain. TRPM8 antagonists are following closely behind for cold allodynia. Early TRPV1 antagonists in the clinic, however, showed worrisome adverse effects including hyperthermia and impaired noxious heat sensation. These adverse effects placed the patients at risk for scalding injury and prompted their withdrawal from the clinical trials. Second generation TRPV1 antagonists that do not cause core body temperature elevation have been reported, although the therapeutic utility of this class of compounds is not yet known. This review discusses the promise and challenges of developing TRP channel antagonists as a new generation of pain therapeutics.


Assuntos
Terapia de Alvo Molecular/métodos , Dor/tratamento farmacológico , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Humanos , Hiperalgesia/tratamento farmacológico , Canais de Potencial de Receptor Transitório/antagonistas & inibidores
18.
J Pharmacol Exp Ther ; 342(2): 416-28, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22570364

RESUMO

The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (≥ 43°C), acidic pH (< 6), and endogenous lipids including N-arachidonoyl dopamine (NADA). Antagonists that block all modes of TRPV1 activation elicit hyperthermia. To identify efficacious TRPV1 antagonists that do not affect temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca(2+) flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain.


Assuntos
Temperatura Corporal/efeitos dos fármacos , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Cálcio/metabolismo , Capsaicina/farmacologia , Linhagem Celular Transformada , Febre/tratamento farmacológico , Febre/fisiopatologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Dor/fisiopatologia , Prótons , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Canais de Cátion TRPV/metabolismo
20.
J Pharmacol Exp Ther ; 341(2): 360-8, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22319196

RESUMO

The transient receptor potential ankyrin-1 (TRPA1) channel has emerged as an attractive target for development of analgesic and anti-inflammatory drugs. However, drug discovery efforts targeting TRPA1 have been hampered by differences between human and rodent species. Many compounds have been identified to have antagonist activity at human TRPA1 (hTRPA1), but when tested at rat TRPA1 (rTRPA1) and mouse TRPA1 (mTRPA1), they show reduced potency as antagonists, no effect, or agonist activity. These compounds are excluded from further drug development because they cannot be tested in preclinical studies using conventional rat/mouse models. To broaden our understanding of species-specific differences, we cloned and functionally characterized rhesus monkey TRPA1 (rhTRPA1) and compared its pharmacological profile to hTRPA1, rTRPA1, and mTRPA1 channels. The functional activities of a diverse group of TRPA1 ligands (both reactive and nonreactive) were determined in a fluorescent Ca²âº influx assay, using transiently transfected human embryonic kidney 293-F cells. 4-Methyl-N-[2,2,2-trichloro-1-(4-nitro-phenylsulfanyl)-ethyl]-benzamide, menthol, and caffeine displayed species-specific differential pharmacology at TRPA1. The pharmacological profile of the rhTRPA1 channel was found to be similar to the hTRPA1 channel. In contrast, the rTRPA1 and mTRPA1 channels closely resembled each other but were pharmacologically distinct from either hTRPA1 or rhTRPA1 channels. Our findings reveal that TRPA1 function differs between primate and rodent species and suggest that rhesus monkey could serve as a surrogate species for humans in preclinical studies.


Assuntos
Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular , DNA Complementar/genética , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Células HEK293 , Haplorrinos , Humanos , Ligantes , Camundongos , Ratos , Especificidade da Espécie , Transfecção , Canais de Potencial de Receptor Transitório/agonistas , Canais de Potencial de Receptor Transitório/antagonistas & inibidores
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