RESUMO
Pulmonary arterial hypertension (PAH) is a progressive disease defined by a chronic elevation in pulmonary arterial pressure with extensive pulmonary vascular remodeling and perivascular inflammation characterized by an accumulation of macrophages, lymphocytes, dendritic cells, and mast cells. Although the exact etiology of the disease is unknown, clinical as well as preclinical data strongly implicate a role for serotonin (5-HT) in the process. Here, we investigated the chronic effects of pharmacological inhibition of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in peripheral 5-HT biosynthesis, in two preclinical models of pulmonary hypertension (PH), the monocrotaline (MCT) rat and the semaxanib (SUGEN, Medinoah, Suzhou, China)-hypoxia rat. In both PH models, ethyl (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate and ethyl (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1 H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, novel orally active TPH1 inhibitors with nanomolar in vitro potency, decreased serum, gut, and lung 5-HT levels in a dose-dependent manner and significantly reduced pulmonary arterial pressure, and pulmonary vessel wall thickness and occlusion in male rats. In the MCT rat model, decreases in lung 5-HT significantly correlated with reductions in histamine levels and mast cell number (P < 0.001, r2 = 0.88). In contrast, neither ambrisentan nor tadalafil, which are vasodilators approved for the treatment of PAH, reduced mast cell number or 5-HT levels, nor were they as effective in treating the vascular remodeling as were the TPH1 inhibitors. When administered in combination with ambrisentan, the TPH1 inhibitors showed an additive effect on pulmonary vascular remodeling and pressures. These data demonstrate that in addition to reducing vascular remodeling, TPH1 inhibition has the added benefit of reducing the perivascular mast cell accumulation associated with PH.
Assuntos
Inibidores Enzimáticos/farmacologia , Hipertensão Pulmonar/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Triptofano Hidroxilase/antagonistas & inibidores , Remodelação Vascular/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Serotonina/sangue , Serotonina/metabolismo , Triptofano Hidroxilase/metabolismoRESUMO
As a follow-up to the discovery of our spirocyclic proline-based TPH1 inhibitor lead, we describe the optimization of this scaffold. Through a combination of X-ray co-crystal structure guided design and an in vivo screen, new substitutions in the lipophilic region of the inhibitors were identified. This effort led to new TPH1 inhibitors with in vivo efficacy when dosed as their corresponding ethyl ester prodrugs. In particular, 15b (KAR5585), the prodrug of the potent TPH1 inhibitor 15a (KAR5417), showed robust reduction of intestinal serotonin (5-HT) levels in mice. Furthermore, oral administration of 15b generated high and sustained systemic exposure of the active parent 15a in rats and dogs. KAR5585 was selected for further pharmacological evaluation in disease models associated with a dysfunctional peripheral 5-HT system.
Assuntos
Pró-Fármacos/química , Prolina/análogos & derivados , Pirimidinas/química , Compostos de Espiro/química , Triptofano Hidroxilase/antagonistas & inibidores , Triptofano Hidroxilase/metabolismo , Animais , Sítios de Ligação , Cães , Meia-Vida , Humanos , Concentração Inibidora 50 , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Prolina/metabolismo , Prolina/farmacologia , Estrutura Terciária de Proteína , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Ratos , Serotonina/metabolismo , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
An increasing number of diseases have been linked to a dysfunctional peripheral serotonin system. Given that tryptophan hydroxylase 1 (TPH1) is the rate limiting enzyme in the biosynthesis off serotonin, it represents an attractive target to regulate peripheral serotonin. Following up to our first disclosure, we report a new chemotype of TPH1 inhibitors where-by the more common central planar heterocycle has been replaced with an open-chain, acyl guanidine surrogate. Through our work, we found that compounds of this nature provide highly potent TPH1 inhibitors with favorable physicochemical properties that were effective in reducing murine intestinal 5-HT in vivo. Furthermore, we obtained a high resolution (1.90Å) X-ray structure crystal structure of one of these inhibitors (compound 51) that elucidated the active conformation along with revealing a dimeric form of TPH1 for the first time.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Guanidina/farmacologia , Triptofano Hidroxilase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Guanidina/síntese química , Guanidina/química , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triptofano Hidroxilase/metabolismoRESUMO
The central role of the biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) as a neurotransmitter with important cognitive and behavioral functions is well known. However, 5-HT produced in the brain only accounts for approximately 5% of the total amount of 5-HT generated in the body. At the onset of our work, it appeared that substituted phenylalanine derivatives or related aryl amino acids were required to produce potent inhibitors of TPH1, as significant losses of inhibitory activity were noted in the absence of this structural element. We disclose herein the discovery of a new class of TPH1 inhibitors that significantly lower peripherally 5-HT.
Assuntos
Prolina/análogos & derivados , Triptofano Hidroxilase/antagonistas & inibidores , Animais , Sítios de Ligação , Encéfalo/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Prolina/síntese química , Prolina/farmacocinética , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Serotonina/metabolismo , Compostos de Espiro/química , Relação Estrutura-Atividade , Triptofano Hidroxilase/metabolismoRESUMO
A novel series of pyrazolo[1,5-a]pyrimidine derivatives was synthesized and evaluated as NPY Y1R antagonists. High binding affinity and selectivity were achieved with C3 trisubstituted aryl groups and C7 substituted 2-(tetrahydro-2H-pyran-4-ylamino)ethylamine moieties. Efforts to find close analogs with low plasma clearance in the rat and minimal p-glycoprotein efflux in the mouse were unsuccessful. Compound 2f (CP-671906) inhibited NPY-induced increases in blood pressure and food intake after iv and icv administration, respectively, in Sprague-Dawley (SD) rat models. Oral administration of compound 2f resulted in a modest, but statistically significant, reduction in food intake in a Wistar rat model of feeding behavior. Small inhibitions of food intake were also observed in an overnight fasting/refeeding model in SD rats. These data suggest a potential role for Y1R in the regulation of food intake in rodents.
Assuntos
Descoberta de Drogas , Ingestão de Alimentos/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Depressores do Apetite/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Humanos , Camundongos , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirazolonas/síntese química , Pirazolonas/química , Pirazolonas/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Ratos , Ratos Sprague-DawleyRESUMO
A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P(1) hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P(1) moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P(1) replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome.
Assuntos
Benzimidazóis/química , Quimases/antagonistas & inibidores , Inibidores de Proteases/química , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Sítios de Ligação , Quimases/metabolismo , Cristalografia por Raios X , Humanos , Interações Hidrofóbicas e Hidrofílicas , Oxirredução , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
Inhibition of sEH is hypothesized to lead to an increase in epoxyeicosatrienoic acids resulting in the potentiation of their anti-inflammatory and vasodilatory effects. In an effort to explore sEH inhibition as an avenue for the development of vasodilatory and cardio- or renal-protective agents, a lead identified through high-throughput screening was optimized, guided by the determination of a solid state co-structure with sEH. Replacement of potential toxicophores was followed by optimization of cell-based potency and ADME properties to provide a new class of functionally potent sEH inhibitors with attractive in vitro metabolic profiles and high and sustained plasma exposures after oral administration in the rat.
Assuntos
Inibidores Enzimáticos/química , Epóxido Hidrolases/antagonistas & inibidores , Piperidinas/química , Ureia/análogos & derivados , Administração Oral , Animais , Sítios de Ligação , Simulação por Computador , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Epóxido Hidrolases/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Ureia/química , Ureia/farmacocinéticaRESUMO
A 270-membered library of trisubstituted ureas was synthesized and evaluated for inhibition of soluble epoxide hydrolase. Library design and reagent selection was guided by the use of a pharmacophore model and synthesis of the array was enabled with a general solid-phase method. This array approach facilitated multi-dimensional SAR around this series and identified functionality responsible for binding affinity, as well as opportunities for modulating the overall in vitro profiles of this class of soluble epoxide hydrolase inhibitors.
Assuntos
Técnicas de Química Combinatória/métodos , Inibidores Enzimáticos/síntese química , Epóxido Hidrolases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Ureia/análogos & derivados , Animais , Humanos , Ligação Proteica , Solubilidade , Relação Estrutura-Atividade , Ureia/químicaRESUMO
Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers. We conducted a high-throughput screen and identified a single selective compound that preferentially inhibited G2019S-LRRK2. Optimization of this scaffold led to a series of novel, potent, and highly selective G2019S-LRRK2 inhibitors.
Assuntos
Indazóis/farmacologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tetrazóis/farmacologia , Animais , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Indazóis/síntese química , Indazóis/farmacocinética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Camundongos , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/farmacocinéticaRESUMO
A series of potent nicotinamide inhibitors of soluble epoxides hydrolase (sEH) is disclosed. This series was designed using structure-based deconstruction and a combination of two HTS hit series, resulting in hybrid analogs that retained the optimal potency from one series, and acceptable in vitro metabolic stability from the other. Structure-guided optimization of these analogs gave rise to nanomolar inhibitors of human sEH that had acceptable plasma exposure to qualify them as probes to determine the in vivo phenotypic consequences of sEH inhibition.
Assuntos
Anti-Inflamatórios/síntese química , Inibidores Enzimáticos/síntese química , Epóxido Hidrolases/antagonistas & inibidores , Niacinamida/síntese química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Niacinamida/química , Niacinamida/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Motivos de Aminoácidos , Anti-Inflamatórios/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Cristalografia por Raios X/métodos , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with K(i) values below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP<5) were discovered.
Assuntos
Química Farmacêutica/métodos , Pirimidinas/química , Pirimidinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Sítios de Ligação , Química Farmacêutica/instrumentação , Desenho de Fármacos , Humanos , Cinética , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-AtividadeRESUMO
A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.
Assuntos
Aminoquinolinas/farmacologia , Química Farmacêutica/métodos , Canais de Cátion TRPV/antagonistas & inibidores , Aminoquinolinas/química , Animais , Cães , Desenho de Fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Inflamação/tratamento farmacológico , Cinética , Modelos Químicos , Conformação Molecular , Dor/tratamento farmacológico , Preparações Farmacêuticas/química , Ratos , Canais de Cátion TRPV/químicaRESUMO
The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.
Assuntos
Desenho de Fármacos , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Ansiedade/tratamento farmacológico , Sítios de Ligação , Técnicas de Química Combinatória , Depressão/tratamento farmacológico , Humanos , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.
Assuntos
Acetamidas/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Descoberta de Drogas , Inibidores de Lipoxigenase/farmacologia , Oxidiazóis/farmacologia , Acetamidas/síntese química , Acetamidas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Modelos Moleculares , Conformação Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-AtividadeRESUMO
Antagonizing the robust stimulation of food intake by neuropeptide Y represents a new potential therapeutic approach for the treatment of obesity. Earlier pharmacological studies have pointed to the Y1 and Y5 receptors as the most likely mediators of the NPY orexigenic response. In this paper, we describe a new series of small molecule Y5 antagonists derived from a 2,4-diaryl-1H-imidazole lead. The main objectives of our structural optimization efforts were to produce novel and potent Y5 antagonists with an improved oral pharmacokinetic profile and less affinity for the hERG potassium channel compared to the lead 2,4-diarylimidazole structures. These goals were accomplished by replacement of the 2-aryl ring with a cyclohexyl ring and subsequent elaboration of the 4-position of the cyclohexyl ring with a variety of hydrophilic functionalities. The resulting compound, N-(2-hydroxy-tert-butyl)(4-[4-[3-(trifluoromethyl)phenyl]imidazol-2-yl]cyclohexyl)carboxamide (20), displayed good potency at the Y5 receptor (K(i) = 3 nM), while interactions at the hERG channel were essentially eliminated (6% inhibition at a concentration of 3 microM). Importantly, the pharmacokinetic properties of 20 (F = 36%) represented a marked improvement over that of the initial 2,4-diarylimidazole structures.
Assuntos
Amidas/síntese química , Cicloexanos/síntese química , Imidazóis/síntese química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Amidas/farmacocinética , Amidas/farmacologia , Animais , Linhagem Celular , Cicloexanos/farmacocinética , Cicloexanos/farmacologia , Desenho de Fármacos , Estabilidade de Medicamentos , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Técnicas de Patch-Clamp , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/fisiologia , Relação Estrutura-AtividadeRESUMO
Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.
Assuntos
Benzimidazóis/química , Fármacos Cardiovasculares/química , Quimases/antagonistas & inibidores , Inibidores de Serina Proteinase/química , Benzimidazóis/síntese química , Benzimidazóis/metabolismo , Fármacos Cardiovasculares/síntese química , Fármacos Cardiovasculares/metabolismo , Domínio Catalítico , Quimases/química , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/metabolismo , Relação Estrutura-AtividadeRESUMO
Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.
Assuntos
Benzamidas/síntese química , Guanidinas/síntese química , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Animais , Benzamidas/química , Benzamidas/farmacologia , Disponibilidade Biológica , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Linhagem Celular , Permeabilidade da Membrana Celular , Tamanho Celular , Inibidores das Enzimas do Citocromo P-450 , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Guanidinas/química , Guanidinas/farmacologia , Humanos , Masculino , Membranas Artificiais , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Permeabilidade , Isoformas de Proteínas/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Trocador 1 de Sódio-Hidrogênio , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography. Compound 59 was characterized as an orally bioavailable, brain penetrant, and highly selective CRF-1 receptor antagonist. Occupancy of rat brain CRF-1 receptors was quantified using ex vivo receptor occupancy assays, using both brain tissue homogenates as well as brain slices receptor autoradiography. Behaviorally, oral administration of 59 significantly antagonized CRF-induced locomotor activity at doses as low as 10 mg/kg and dose-dependently reduced the restraint stress-induced ACTH increases.
Assuntos
Pirazinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Tecido Adiposo/metabolismo , Administração Oral , Hormônio Adrenocorticotrópico/sangue , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Córtex Cerebral/metabolismo , Humanos , Técnicas In Vitro , Injeções Intraventriculares , Masculino , Microssomos Hepáticos/metabolismo , Atividade Motora/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacologia , Ensaio Radioligante , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Restrição Física , Relação Estrutura-AtividadeRESUMO
The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.