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1.
Clin Drug Investig ; 40(7): 603-615, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32399853

RESUMO

BACKGROUND AND OBJECTIVE: SUVN-G3031 is a novel, potent, and selective histamine-3 receptor (H3R) inverse agonist in development for the treatment of narcolepsy. Our objective was to characterize the safety, tolerability, and pharmacokinetics of SUVN-G3031 in healthy young adults after single and multiple doses, and to evaluate the effect of food, gender, and age on the pharmacokinetics. METHODS: A single ascending dose (SAD) and a multiple ascending dose (MAD) study for 14 days was conducted in healthy young adults using a randomized, double-blind study design. The effect of food, gender, and age on SUVN-G3031 pharmacokinetics (6 mg as a single dose) was evaluated using an open-label, two-period, randomized, crossover design in fed and fasted states. Pharmacokinetics and safety assessments were conducted throughout the study. RESULTS: Single doses of SUVN-G3031 up to 20 mg and multiple doses up to 6 mg once daily were found to be safe and well tolerated in healthy young adults. The most frequently reported adverse events were abnormal dreams, dyssomnia, and hot flushes. SUVN-G3031 exposure was dose proportional across the tested doses. Steady state was achieved on day 6 after once-daily dosing. Renal excretion (~ 60%) of unchanged SUVN-G3031 was the major route of elimination. Food, gender, and age did not have any clinically meaningful effect on SUVN-G3031 exposure. CONCLUSION: SUVN-G3031 was found to be safe and well tolerated in healthy human subjects without any effect of age, gender, and food on the pharmacokinetics and safety profile. Clinical Trials Registration (https://clinicaltrials.gov): NCT04072380 and NCT02342041.


Assuntos
Morfolinas/efeitos adversos , Narcolepsia/tratamento farmacológico , Piperidinas/efeitos adversos , Administração Oral , Adulto , Estudos Cross-Over , Método Duplo-Cego , Agonismo Inverso de Drogas , Feminino , Voluntários Saudáveis , Histamina , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/farmacocinética , Piperidinas/farmacocinética
2.
Nature ; 580(7805): 621-627, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32179876

RESUMO

Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules1-3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/síntese química , Carbono/química , Técnicas de Química Sintética , Hidrogênio/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/síntese química , Androstenos/síntese química , Androstenos/química , Catálise , Agonismo Inverso de Drogas , Elétrons , Flúor/química , Hidroxilação , Ácidos de Lewis/química , Manganês/química , Metilação , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Oxazolidinonas/síntese química , Oxazolidinonas/química , Oxirredução , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Tetrazóis/síntese química , Tetrazóis/química
3.
J Med Chem ; 63(8): 4349-4369, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32202101

RESUMO

Muscarinic M3 receptor antagonists and inverse agonists displaying high affinity and subtype selectivity over the antitarget M2 are valuable pharmacological tools and may enable improved treatment of chronic obstructive pulmonary disease (COPD), asthma, or urinary incontinence. On the basis of known M3 antagonists comprising a piperidine or quinuclidine unit attached to a biphenyl carbamate, 5-fluoro substitution was responsible for M3 subtype selectivity over M2, while 3'-chloro substitution substantially increased affinity through a σ-hole interaction. Resultantly, two piperidinyl- and two quinuclidinium-substituted biphenyl carbamates OFH243 (13n), OFH244 (13m), OFH3911 (14n), and OFH3912 (14m) were discovered, which display two-digit picomolar affinities with Ki values from 0.069 to 0.084 nM, as well as high selectivity over the M2 subtype (46- to 68-fold). While weak inverse agonistic properties were determined for the biphenyl carbamates 13m and 13n, neutral antagonism was observed for 14m and 14n and tiotropium under identical assay conditions.


Assuntos
Compostos de Aminobifenil/química , Agonismo Inverso de Drogas , Halogênios/química , Agonistas Muscarínicos/química , Antagonistas Muscarínicos/química , Receptor Muscarínico M3/agonistas , Receptor Muscarínico M3/antagonistas & inibidores , Compostos de Aminobifenil/farmacologia , Animais , Células CACO-2 , Células HEK293 , Halogênios/farmacologia , Humanos , Masculino , Simulação de Acoplamento Molecular/métodos , Agonistas Muscarínicos/metabolismo , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M3/metabolismo
4.
Molecules ; 25(4)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085406

RESUMO

(1) Background: Acute administration of the cannabinoid receptor 1 (CB1R) inverse agonist Rimonabant (SR141716A) to fed Wistar rats was shown to elicit a rapid and short-lasting elevation of serum free fatty acids. (2) Methods: The effect of Rimonabant on lipolysis in isolated primary rat adipocytes was studied to raise the possibility for direct mechanisms not involving the (hypothalamic) CB1R. (3) Results: Incubation of these cells with Rimonabant-stimulated lipolysis to up to 25% of the maximal isoproterenol effect, which was based on both CB1R-dependent and independent mechanisms. The CB1R-dependent one was already effective at Rimonabant concentrations of less than 1 µM and after short-term incubation, partially additive to ß-adrenergic agonists and blocked by insulin and, in part, by adenosine deaminase, but not by propranolol. It was accompanied by protein kinase A (PKA)-mediated association of hormone-sensitive lipase (HSL) with lipid droplets (LD) and dissociation of perilipin-1 from LD. The CB1R-independent stimulation of lipolysis was observed only at Rimonabant concentrations above 1 µM and after long-term incubation and was not affected by insulin. It was recapitulated by a cell-free system reconstituted with rat adipocyte LD and HSL. Rimonabant-induced cell-free lipolysis was not affected by PKA-mediated phosphorylation of LD and HSL, but abrogated by phospholipase digestion or emulsification of the LD. Furthermore, LD isolated from adipocytes and then treated with Rimonabant (>1 µM) were more efficient substrates for exogenously added HSL compared to control LD. The CB1R-independent lipolysis was also demonstrated in primary adipocytes from fed rats which had been treated with a single dose of Rimonabant (30 mg/kg). (4) Conclusions: These data argue for interaction of Rimonabant (at high concentrations) with both the LD surface and the CB1R of primary rat adipocytes, each leading to increased access of HSL to LD in phosphorylation-independent and dependent fashion, respectively. Both mechanisms may lead to direct and acute stimulation of lipolysis at peripheral tissues upon Rimonabant administration and represent targets for future obesity therapy which do not encompass the hypothalamic CB1R.


Assuntos
Adipócitos/metabolismo , Agonismo Inverso de Drogas , Lipólise , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto/farmacologia , Adipócitos/efeitos dos fármacos , Animais , Sistema Livre de Células , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ativação Enzimática/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Ratos Wistar , Esterol Esterase/metabolismo
5.
Nature ; 579(7800): 609-614, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32040955

RESUMO

The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle1-4. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep5,6 and depression1-4,7-9. Despite their importance, few in vivo active MT1-selective ligands have been reported2,8,10-12, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT1 inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT1-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.


Assuntos
Ritmo Circadiano/fisiologia , Ligantes , Receptores de Melatonina/agonistas , Receptores de Melatonina/metabolismo , Animais , Ritmo Circadiano/efeitos dos fármacos , Escuridão , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Feminino , Humanos , Luz , Masculino , Camundongos , Camundongos Knockout , Simulação de Acoplamento Molecular , Receptor MT1 de Melatonina/agonistas , Receptor MT1 de Melatonina/deficiência , Receptor MT1 de Melatonina/genética , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/agonistas , Receptor MT2 de Melatonina/deficiência , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo , Receptores de Melatonina/deficiência , Receptores de Melatonina/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Especificidade por Substrato/genética
6.
Expert Rev Clin Pharmacol ; 13(2): 79-84, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31937172

RESUMO

Introduction: Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep, hypnagogic hallucinations, and sleep paralysis. Pitolisant is a first-in-class drug acting on histamine 3 receptors and indicated for the treatment of narcolepsy. This article aims to review pitolisant.Areas covered: In this paper the chemical properties, mechanism of action, pharmacokinetics, clinical efficacy and safety of pitolisant was introduced, and the development course of drugs for treating narcolepsy is also briefly described. We performed a systematic review of the literature using PubMed and the following keywords were used: 'pitolisant' and 'narcolepsy', 'cataplexy' and 'excessive daytime sleepiness' and 'histamine 3 receptor'.Expert opinion: Pitolisant is a histamine 3 receptor antagonist/inverse agonist. It can activate histamine release in the brain and enhances wakefulness. Clinical studies showed that pitolisant significantly decreased excessive daytime sleepiness and cataplexy rate versus placebo. Pitolisant was well tolerated, common adverse reactions were headache, insomnia, nausea, and anxiety.


Assuntos
Narcolepsia/tratamento farmacológico , Piperidinas/administração & dosagem , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Cataplexia/tratamento farmacológico , Cataplexia/fisiopatologia , Agonismo Inverso de Drogas , Agonistas dos Receptores Histamínicos/administração & dosagem , Agonistas dos Receptores Histamínicos/efeitos adversos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/efeitos adversos , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Narcolepsia/fisiopatologia , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Receptores Histamínicos H3/metabolismo
7.
J Med Chem ; 63(1): 241-259, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31821760

RESUMO

Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric inhibition. Here, we report a highly efficient in silico-guided approach that led to the discovery of novel allosteric RORγt inverse agonists with a distinct isoxazole chemotype. The the most potent compound, 25 (FM26), displayed submicromolar inhibition in a coactivator recruitment assay and effectively reduced IL-17a mRNA production in EL4 cells, a marker of RORγt activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and cocrystallization with the RORγt ligand binding domain. The isoxazole compounds have promising pharmacokinetic properties comparable to other allosteric ligands but with a more diverse chemotype. The efficient ligand-based design approach adopted demonstrates its versatility in generating chemical diversity for allosteric targeting of RORγt.


Assuntos
Isoxazóis/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Reação de Cicloadição , Desenho de Fármacos , Agonismo Inverso de Drogas , Isoxazóis/síntese química , Isoxazóis/metabolismo , Ligantes , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Relação Estrutura-Atividade
8.
Annu Rev Pharmacol Toxicol ; 60: 371-390, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31386594

RESUMO

Retinoic acid-related orphan receptor γt (RORγt) functions as a ligand-dependent transcription factor that regulates multiple proinflammatory genes and plays a critical role in several inflammatory and autoimmune diseases. Various endogenous and synthetic RORγ (inverse) agonists have been identified that regulate RORγ transcriptional activity, including many cholesterol intermediates and oxysterols. Changes in cholesterol biosynthesis and metabolism can therefore have a significant impact on the generation of oxysterol RORγ ligands and, consequently, can control RORγt activity and inflammation. These observations contribute to a growing literature that connects cholesterol metabolism to the regulation of immune responses and autoimmune disease. Loss of RORγ function in knockout mice and in mice treated with RORγ inverse agonists results in reduced production of proinflammatory cytokines, such as IL-17A/F, and increased resistance to autoimmune disease in several experimental rodent models. Thus, RORγt inverse agonists might provide an attractive therapeutic approach to treat a variety of autoimmune diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Inflamação/tratamento farmacológico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Animais , Doenças Autoimunes/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Agonismo Inverso de Drogas , Humanos , Inflamação/imunologia , Ligantes , Camundongos , Camundongos Knockout
9.
Molecules ; 24(24)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31835873

RESUMO

Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H3 receptor (H3R). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate H3R ligand 44. It shows high reactivity toward glutathione combined with appropriate stability in water and reacts selectively with the cysteine sidechain in a model nonapeptide equipped with nucleophilic residues. The covalent interaction of 44 with H3R was validated with washout experiments and leads to inverse agonism on H3R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H3R conformation and to study the consequences of prolonged inhibition of the H3R.


Assuntos
Isotiocianatos/síntese química , Receptores Histamínicos H3/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Agonismo Inverso de Drogas , Células HEK293 , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Isotiocianatos/química , Isotiocianatos/farmacologia , Ligantes , Receptores Histamínicos H3/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
10.
Biochem Pharmacol ; 170: 113647, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31585071

RESUMO

G protein-coupled receptors (GPCRs) participate in many pathophysiological processes as well as almost all aspects of normal physiology. They are present at the surface of all cell types making them amenable and attractive targets for pharmaceutical therapeutics. GPCRs possess complex pharmacology with the ability to be turned on to various extents, have their constitutive activity suppressed and even switch between signaling pathways to which they couple. Underlying this complex pharmacology is GPCR signaling efficacy, and differences in efficacy promoted by alternative ligands and in different tissues is of great interest to biology in general and also the pharmaceutical industry. In this review we hope to discuss what the molecular foundations of efficacy are and whether a new approach utilizing a rate-dependent model may provide new insights into this phenomenon.


Assuntos
Preparações Farmacêuticas/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/fisiologia , Animais , Agonismo Inverso de Drogas , Humanos , Ligantes , Preparações Farmacêuticas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
11.
Neurosci Lett ; 713: 134524, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31585211

RESUMO

Previous work has shown that chronic nicotine administration causes adaptive changes in 5-HT2A receptor expression. Based on this relationship, it was hypothesized that inactivating 5-HT2A receptors with the inverse agonists pimavanserin and volinanserin (MDL100907), would reduce the symptoms of nicotine withdrawal syndrome. Sprague-Dawley rats were rendered nicotine-dependent by subcutaneous infusion of nicotine bitartrate, 9 mg/kg/day for seven days. The infusions were then terminated, and 22 h later, rats were observed under "blind" conditions for somatically expressed behavioral nicotine withdrawal signs. One hour before observations, the nicotine dependent rats were injected i.p. with saline alone, or either 0.3 or 1.0 mg/kg pimavanserin in saline. Total withdrawal signs were reduced in a dose-dependent manner. A one-way ANOVA (total withdrawal signs as a function of dose) was highly significant, as was the descending linear trend of withdrawal signs as a function of dose. The 1.0 mg/kg dose reduced withdrawal signs nearly to the level exhibited by a comparison group of non-dependent rats injected with saline. A second experiment was conducted in a similar manner, which showed that volinanserin at 1.0 mg/kg but not 0.25 mg/kg also reduced nicotine withdrawal signs to nearly the level of non-dependent rats. In vitro experiments demonstrated that both pimavanserin and volinanserin potently antagonize 5-HT2A receptors, with approximately 25-fold, and 300-fold selectivity over 5-HT2C receptors, respectively. The results suggest that the 5-HT2A receptor contributes to mediating nicotine withdrawal syndrome, and thus represents a potential target for interventions to aid smoking cessation.


Assuntos
Fluorbenzenos/farmacologia , Nicotina/efeitos adversos , Piperidinas/farmacologia , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/prevenção & controle , Ureia/análogos & derivados , Animais , Relação Dose-Resposta a Droga , Agonismo Inverso de Drogas , Masculino , Ratos , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Ureia/farmacologia
12.
J Med Chem ; 62(21): 9931-9946, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31638797

RESUMO

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.


Assuntos
Desenho de Fármacos , Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacologia , Animais , Humanos , Células Jurkat , Camundongos , Modelos Moleculares , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Conformação Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual
13.
Food Chem Toxicol ; 133: 110792, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31472229

RESUMO

Parabens are widely used as preservatives in personal care products, medicines and foods, resulting in substantial human exposures, even though some harmful effects, such as endocrine-disrupting activity, have been reported. Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα), which are members of the nuclear receptor superfamily, regulate the metabolism of endogenous substrates including hormones. Therefore, we hypothesized that parabens may alter hormone-metabolizing activities by acting on these receptors, and such changes could contribute to the endocrine-disrupting activity. To test this idea, we systematically examined the effects of 17 parabens on these receptors using reporter gene assays. Nine parabens significantly activated human and rat PXR. Parabens with C2-C5 (linear and branched) side chains were most active. Butylparaben and isobutylparaben also significantly activated rat CAR. We found that long-side-chain (C7-C12) parabens showed up to 2-fold activation of PPARα at 10 µM. Furthermore, pentylparaben and hexylparaben showed rat PXR antagonistic activity and rat CAR inverse agonistic activity. The activity of butylparaben towards PXR and CAR was lost after carboxylesterase-mediated metabolism. These findings confirm that parabens influence the activities of PXR, CAR and PPARα, and thus have the potential to contribute to endocrine disruption by altering hormone metabolism.


Assuntos
PPAR alfa/metabolismo , Parabenos/farmacologia , Receptor de Pregnano X/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Ativação Transcricional/efeitos dos fármacos , Animais , Agonismo Inverso de Drogas , Humanos , Masculino , Microssomos Hepáticos/metabolismo , PPAR alfa/agonistas , PPAR alfa/genética , Parabenos/metabolismo , Receptor de Pregnano X/antagonistas & inibidores , Receptor de Pregnano X/genética , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/genética
14.
ACS Chem Neurosci ; 10(9): 3939-3945, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31397148

RESUMO

Our previous results showed that naltrindole (NTI) derivatives with certain types of electron-withdrawing groups as an N-substituent showed δ opioid receptor (DOR) inverse agonistic activities. We therefore synthesized N-acylated NTI derivatives 3a-e and observed that N-benzoyl and N-cyclopropanecarbonyl derivatives SYK-736 (3b) and SYK-623 (3c) were DOR full inverse agonists and the N-acryloyl derivative 3d was a DOR partial inverse agonist. SKY-623 was over 110-fold more potent than the reference compound ICI-174,864. Both naltriben (NTB) and 7-benzylidenenaltrexone (BNTX) derivatives with N-benzoyl and N-cyclopropanecarbonyl groups were also DOR full inverse agonists. These N-acylated inverse agonists are interesting compounds because they have no basic nitrogen atom, which has been demonstrated to be an important pharmacophore. NTI and BNTX-type DOR inverse agonists SYK-623 and SYK-723 (12c) showed dose-dependent antitussive effects in a mouse cough model induced by citric acid exposure. The antitussive effects by SYK-623 and SYK-723 were significantly attenuated by pretreatment with DOR agonist SNC80.


Assuntos
Analgésicos Opioides/uso terapêutico , Antitussígenos/uso terapêutico , Desenvolvimento de Medicamentos/métodos , Agonismo Inverso de Drogas , Nitrogênio , Receptores Opioides delta/agonistas , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Animais , Antitussígenos/química , Antitussígenos/metabolismo , Ácido Cítrico/toxicidade , Tosse/induzido quimicamente , Tosse/tratamento farmacológico , Tosse/metabolismo , Relação Dose-Resposta a Droga , Camundongos , Receptores Opioides delta/metabolismo
15.
Acta Pharmacol Sin ; 40(11): 1480-1489, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31316175

RESUMO

The retinoic acid receptor-related orphan receptor (ROR) γt receptor is a member of nuclear receptors, which is indispensable for the expression of pro-inflammatory cytokine IL-17. RORγt has been established as a drug target to design and discover novel treatments for multiple inflammatory and immunological diseases. It is important to elucidate the molecular mechanisms of how RORγt is activated by an agonist, and how the transcription function of RORγt is interrupted by an inverse agonist. In this study we performed molecular dynamics simulations on four different RORγt systems, i.e., the apo protein, protein bound with agonist, protein bound with inverse agonist in the orthosteric-binding pocket, and protein bound with inverse agonist in the allosteric-binding pocket. We found that the orthosteric-binding pocket in the apo-form RORγt was mostly open, confirming that apo-form RORγt was constitutively active and could be readily activated (ca. tens of nanoseconds scale). The tracked data from MD simulations supported that RORγt could be activated by an agonist binding at the orthosteric-binding pocket, because the bound agonist helped to enhance the triplet His479-Tyr502-Phe506 interactions and stabilized H12 structure. The stabilized H12 helped RORγt to form the protein-binding site, and therefore made the receptor ready to recruit a coactivator molecule. We also showed that transcription function of RORγt could be interrupted by the binding of inverse agonist at the orthosteric-binding pocket or at the allosteric-binding site. After the inverse agonist was bound, H12 either structurally collapsed, or reorientated to a different position, at which the presumed protein-binding site was not able to be formed.


Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Sítio Alostérico , Anilidas/metabolismo , Agonismo Inverso de Drogas , Humanos , Indazóis/metabolismo , Simulação de Dinâmica Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligação Proteica , Piridinas/metabolismo
16.
Commun Biol ; 2: 236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263780

RESUMO

Endothelin receptors (ETA and ETB) are G-protein-coupled receptors activated by endothelin-1 and are involved in blood pressure regulation. IRL2500 is a peptide-mimetic of the C-terminal tripeptide of endothelin-1, and has been characterized as a potent ETB-selective antagonist, which has preventive effects against brain edema. Here, we report the crystal structure of the human ETB receptor in complex with IRL2500 at 2.7 Å-resolution. The structure revealed the different binding modes between IRL2500 and endothelin-1, and provides structural insights into its ETB-selectivity. Notably, the biphenyl group of IRL2500 penetrates into the transmembrane core proximal to D2.50, thus stabilizing the inactive conformation. Using the newly-established constitutively active mutant, we clearly demonstrate that IRL2500 functions as an inverse agonist for the ETB receptor. The current findings will expand the chemical space of ETR antagonists and facilitate the design of inverse agonists for other class A GPCRs.


Assuntos
Compostos de Bifenilo/química , Dipeptídeos/química , Antagonistas dos Receptores de Endotelina/química , Receptor de Endotelina B/química , Sítios de Ligação , Bosentana/química , Cristalização , Cristalografia por Raios X , Desenho de Fármacos , Agonismo Inverso de Drogas , Endotelina-1/química , Humanos
17.
Bioorg Med Chem Lett ; 29(16): 2265-2269, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31257087

RESUMO

An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.


Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacologia , Sulfonas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Agonismo Inverso de Drogas , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Relação Estrutura-Atividade , Sulfonas/administração & dosagem , Sulfonas/química
18.
J Med Chem ; 62(13): 6330-6345, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185168

RESUMO

Peripherally restricted CB1 receptor antagonists may be useful in treating metabolic syndrome, diabetes, liver diseases, and gastrointestinal disorders. Clinical development of the centrally acting CB1 inverse agonist otenabant (1) was halted due to its potential of producing adverse effects. SAR studies of 1 are reported herein with the objective of producing peripherally restricted analogues. Crystal structures of hCB1 and docking studies with 1 indicate that the piperidine group could be functionalized at the 4-position to access a binding pocket that can accommodate both polar and nonpolar groups. The piperidine is studied as a linker, functionalized with alkyl, heteroalkyl, aryl, and heteroaryl groups using a urea connector. Orally bioavailable and peripherally selective compounds have been produced that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. Compound 38 blocked alcohol-induced liver steatosis in mice and has good ADME properties for further development.


Assuntos
Antagonistas de Receptores de Canabinoides/farmacologia , Piperidinas/farmacologia , Purinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Animais , Antagonistas de Receptores de Canabinoides/síntese química , Antagonistas de Receptores de Canabinoides/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Agonismo Inverso de Drogas , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Feminino , Humanos , Fígado/patologia , Células Madin Darby de Rim Canino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/metabolismo , Purinas/síntese química , Purinas/metabolismo , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade
19.
Cell Death Dis ; 10(6): 416, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138790

RESUMO

Growing evidence indicates that clear cell renal cell carcinoma (ccRCC) is a metabolism-related disease. Changes in fatty acid (FA) and cholesterol metabolism play important roles in ccRCC development. As a nuclear transcription factor receptor, Liver X receptor (LXR) regulates a variety of key molecules associated with FA synthesis and cholesterol transport. Therefore, targeting LXR may provide new therapeutic targets for ccRCC. However, the potential regulatory effect and molecular mechanisms of LXR in ccRCC remain unknown. In the present study, we found that both an LXR agonist and an XLR inverse agonist could inhibit proliferation and colony formation and induce apoptosis in ccRCC cells. We observed that the LXR agonist LXR623 downregulated the expression of the low-density lipoprotein receptor (LDLR) and upregulated the expression of ABCA1, which resulted in reduced intracellular cholesterol and apoptosis. The LXR inverse agonist SR9243 downregulated the FA synthesis proteins sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FASN) and stearoyl-coA desaturase 1 (SCD1), causing a decrease in intracellular FA content and inducing apoptosis in ccRCC cells. SR9243 and LXR623 induced apoptosis in ccRCC cells but had no killing effect on normal renal tubular epithelial HK2 cells. We also found that SRB1-mediated high-density lipoprotein (HDL) in cholesterol influx is the cause of high cholesterol in ccRCC cells. In conclusion, our data suggest that an LXR inverse agonist and LXR agonist decrease the intracellular FA and cholesterol contents in ccRCC to inhibit tumour cells but do not have cytotoxic effects on non-malignant cells. Thus, LXR may be a safe therapeutic target for treating ccRCC patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indazóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Receptores X do Fígado/agonistas , Sulfonamidas/uso terapêutico , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Colesterol/metabolismo , Agonismo Inverso de Drogas , Ácidos Graxos/metabolismo , Humanos , Indazóis/farmacologia , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Camundongos , Camundongos Nus , Receptores de LDL/metabolismo , Sulfonamidas/farmacologia , Transplante Heterólogo
20.
Bioorg Med Chem Lett ; 29(14): 1799-1806, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31101472

RESUMO

A high-throughput screen against Inventiva's compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein.


Assuntos
Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Quinolinas/química , Animais , Modelos Animais de Doenças , Humanos , Camundongos
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