RESUMEN
A series of 1,4-benzoxazin-3-one analogs were investigated to discover mode-selective TRPV1 antagonists, since such antagonists are predicted to minimize target-based adverse effects. Using the high-affinity antagonist 2 as the lead structure, the structure activity relationship was studied by modifying the A-region through incorporation of a polar side chain on the benzoxazine and then by changing the C-region with a variety of substituted pyridine, pyrazole and thiazole moieties. The t-butyl pyrazole and thiazole C-region analogs provided high potency as well as mode-selectivity. Among them, antagonist 36 displayed potent and capsaicin-selective antagonism with IC50 = 2.31 nM for blocking capsaicin activation and only 47.5 % inhibition at 3 µM concentration toward proton activation, indicating that more than a 1000-fold higher concentration of 36 was required to inhibit proton activation than was required to inhibit capsaicin activation. The molecular modeling study of 36 with our homology model indicated that two π-π interactions with the Tyr511 and Phe591 residues by the A- and C-region and hydrogen bonding with the Thr550 residue by the B-region were critical for maintaining balanced and stable binding. Systemic optimization of antagonist 2, which has high-affinity but full antagonism for activators of all modes, led to the mode-selective antagonist 36 which represents a promising step in the development of clinical TRPV1 antagonists minimizing side effects such as hyperthermia and impaired heat sensation.
Asunto(s)
Benzoxazinas , Canales Catiónicos TRPV , Urea , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Relación Estructura-Actividad , Benzoxazinas/química , Benzoxazinas/farmacología , Benzoxazinas/síntesis química , Urea/análogos & derivados , Urea/química , Urea/farmacología , Urea/síntesis química , Humanos , Estructura Molecular , Animales , Capsaicina/farmacología , Capsaicina/química , Descubrimiento de Drogas , Relación Dosis-Respuesta a DrogaRESUMEN
To discover mode-selective TRPV1 antagonists as thermoneutral drug candidates, the previous potent antagonist benzopyridone 2 was optimized based on the pharmacophore A- and C-regions. The structure activity relationship was investigated systematically by modifying the A-region by incorporating a polar side chain on the pyridone and then by changing the C-region with a variety of substituted pyridine and pyrazole moieties. The 3-t-butyl and 3-(1-methylcyclopropyl) pyrazole C-region analogs provided high potency as well as mode-selectivity. Among them, 51 and 54 displayed potent and capsaicin-selective antagonism with IC50 = 2.85 and 3.27 nM to capsaicin activation and 28.5 and 31.5 % inhibition at 3 µM concentration toward proton activation, respectively. The molecular modeling study of 51 with our homology model indicated that the hydroxyethyl side chain in the A-region interacted with Arg557 and Glu570, the urea B-region engaged in hydrogen bonding with Tyr511 and Thr550, respectively, and the pyrazole C-region made two hydrophobic interactions with the receptor. Optimization of antagonist 2, which has full antagonism for activators of all modes, lead to mode-selective antagonists 51 and 54. These observations will provide insight into the future development of clinical TRPV1 antagonists without target-based side effects.
Asunto(s)
Capsaicina , Urea , Urea/química , Capsaicina/farmacología , Relación Estructura-Actividad , Modelos Moleculares , Pirazoles/farmacología , Canales Catiónicos TRPVRESUMEN
Munc13-1 is a key protein necessary for vesicle fusion and neurotransmitter release in the brain. Diacylglycerol (DAG)/phorbol ester binds to its C1 domain in the plasma membrane and activates it. The C1 domain of Munc13-1 and protein kinase C (PKC) are homologous in terms of sequence and structure. In order to identify small-molecule modulators of Munc13-1 targeting the C1 domain, we studied the effect of three DAG-lactones, (R,Z)-(2-(hydroxymethyl)-4-(3-isobutyl-5-methylhexylidene)-5-oxotetrahydrofuran-2-yl)methyl pivalate (JH-131e-153), (E)-(2-(hydroxymethyl)-4-(3-isobutyl-5-methylhexylidene)-5-oxotetrahydrofuran-2-yl)methyl pivalate (AJH-836), and (E)-(2-(hydroxymethyl)-4-(4-nitrobenzylidene)-5-oxotetrahydrofuran-2-yl)methyl 4-(dimethylamino)benzoate (130C037), on Munc13-1 activation using the ligand-induced membrane translocation assay. JH-131e-153 showed higher activation than AJH-836, and 130C037 was not able to activate Munc13-1. To understand the role of the ligand-binding site residues in the activation process, three alanine mutants were generated. For AJH-836, the order of activation was wild-type (WT) Munc13-1 > R592A > W588A > I590A. For JH-131e-153, the order of activation was WT > I590 ≈ R592A ≈ W588A. Overall, the Z isomer of DAG-lactones showed higher potency than the E isomer and Trp-588, Ile-590, and Arg-592 were important for its binding. When comparing the activation of Munc13-1 and PKC, the order of activation for JH-131e-153 was PKCα > Munc13-1 > PKCε and for AJH-836, the order of activation was PKCε > PKCα > Munc13-1. Molecular docking supported higher binding of JH-131e-153 than AJH-836 with the Munc13-1 C1 domain. Our results suggest that DAG-lactones have the potential to modulate neuronal processes via Munc13-1 and can be further developed for therapeutic intervention for neurodegenerative diseases.
Asunto(s)
Diglicéridos , Proteína Quinasa C-alfa , Ligandos , Simulación del Acoplamiento Molecular , Proteína Quinasa C , Lactonas/farmacologíaRESUMEN
The natural products neorautenol and shinpterocarpin and their structural analogs were investigated as novel anticancer agents. Twenty-four analogs, including analogs containing a polar chain and simplified analogs, were synthesized efficiently by a modified method from previous reports. The antitumor screening of synthesized compounds toward six cancer cell lines indicated that compounds 37, 42 and 43 with a dialkylaminoethyl-type side chain exhibited more promising activity than neorautenol and shinpterocarpin against lung and colon cancer lines with a range of 4-9 µM. They showed selective toxicity in normal cells.
Asunto(s)
Antineoplásicos , Estructura Molecular , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular TumoralRESUMEN
A series of N-benzyl 5-(4-sulfamoylbenzylidene-2-thioxothiazolidin-4-one analogs, designed as hybrids of CY09 and JC121, were investigated as inhibitors of NLRP3 inflammasome activation. Among them, compounds 34 and 36 were identified as promising NLRP3 inhibitors by measuring the amount of active caspase-1 p20 and IL-1ß produced by NLRP3 inflammasome activation. Further studies indicated that both compounds inhibited NLRP3 inflammasome assembly by reducing the formation of NLRP3 and ASC oligomer specks and selectively inhibited only NLRP3 inflammasome activation and not other inflammasomes such as NLRC4 and AIM2.
Asunto(s)
Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Caspasa 1 , Proteínas de Unión al ADN , Interleucina-1betaRESUMEN
Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous cellular functions, making them extensively studied and highly attractive drug targets. In our previous work, we identified in racemate 1-2, based on the 2-benzyl-3-hydroxypropyl ester scaffold, two new potent and promising PKCα and PKCδ ligands, targeting the C1 domain of these two kinases. Herein, we report the resolution of the racemates by enantioselective semi-preparative HPLC. The attribution of the absolute configuration (AC) of homochirals 1 was performed by NMR, via methoxy-α-trifluoromethyl-α-phenylacetic acid derivatization (MTPA or Mosher's acid). Moreover, the match between the experimental and predicted electronic circular dichroism (ECD) spectra confirmed the assigned AC. These results proved that Mosher's esters can be properly exploited for the determination of the AC also for chiral primary alcohols. Lastly, homochiral 1 and 2 were assessed for binding affinity and functional activity against PKCα. No significative differences in the Ki of the enantiopure compounds was observed, thus suggesting that chirality does not seem to play a significant role in targeting PKC C1 domain. These results are in accordance with the molecular docking studies performed using a new homology model for the human PKCαC1B domain.
Asunto(s)
Ésteres , Proteína Quinasa C-alfa , Cromatografía Líquida de Alta Presión/métodos , Humanos , Simulación del Acoplamiento Molecular , EstereoisomerismoRESUMEN
A series of O-substituted analogs of the C-ring-truncated scaffold of deguelin designed as heat shock protein 90 (HSP90) C-terminal inhibitors were investigated as novel antitumor agents against human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Among the synthesized compounds, compound 37 displayed significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells with little cytotoxicity to normal cells. Mechanistic studies of compound 37 carried out by HSP90α C-terminal inhibitor screening, the induction of the heat shock response and downregulation of HSP90 client proteins indicated that the antitumor activity of 37 in breast cancer cells could be attributed to the destabilization and inactivation of HSP90 client proteins by the binding of 37 to the C-terminal domain of HSP90. A molecular docking study of compound 37 with a HSP90 homology model indicated that its S-isomer fit well in the ATP binding site of the C-terminal domain, forming key interactions.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Descubrimiento de Drogas , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Rotenona/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Rotenona/síntesis química , Rotenona/química , Rotenona/farmacología , Relación Estructura-ActividadRESUMEN
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are rate-limiting enzymes in the kynurenine pathway (KP) of l-tryptophan (l-Trp) metabolism and are becoming key drug targets in the combination therapy of checkpoint inhibitors in immunoncology. To discover a selective and potent IDO1 inhibitor, a structure-activity relationship (SAR) study of N-hydroxybenzofuran-5-carboximidamide as a novel scaffold was investigated in a systematic manner. Among the synthesized compounds, the N-3-bromophenyl derivative 19 showed the most potent inhibition, with an IC50 value of 0.44 µM for the enzyme and 1.1 µM in HeLa cells. The molecular modeling of 19 with the X-ray crystal structure of IDO1 indicated that dipole-ionic interactions with heme iron, halogen bonding with Cys129 and the two hydrophobic interactions were important for the high potency of 19.
Asunto(s)
Amidinas/farmacología , Benzofuranos/farmacología , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Oximas/farmacología , Amidinas/síntesis química , Amidinas/metabolismo , Benzofuranos/síntesis química , Benzofuranos/metabolismo , Dominio Catalítico , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Células HeLa , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Oximas/síntesis química , Oximas/metabolismo , Unión Proteica , Electricidad Estática , Relación Estructura-ActividadRESUMEN
A series consisting of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists. The structure-activity analysis targeting their three pharmacophoric regions indicated that halogenated phenyl A-region analogs exhibited a broad functional profile ranging from agonism to antagonism. Among the compounds, antagonists 28 and 92 exhibited potent antagonism toward capsaicin for hTRPV1 with Ki[CAP] = 2.6 and 6.9 nM, respectively. Further, antagonist 92 displayed promising analgesic activity in vivo in both phases of the formalin mouse pain model. A molecular modeling study of 92 indicated that the two fluoro groups in the A-region made hydrophobic interactions with the receptor.
Asunto(s)
Acetamidas/farmacología , Amidas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Acetamidas/síntesis química , Acetamidas/química , Amidas/síntesis química , Amidas/química , Animales , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
Trastuzumab resistance in HER2-positive breast cancer is associated with a poorer prognosis. HSP90 is thought to play a major role in such resistance, but N-terminal inhibitors of this target have had little success. We sought to investigate the utility of NCT-547, a novel, rationally-designed C-terminal HSP90 inhibitor in the context of overcoming trastuzumab resistance. NCT-547 treatment significantly induced apoptosis without triggering the heat shock response (HSR), accompanied by caspase-3/- 7 activation in both trastuzumab-sensitive and -resistant cells. NCT-547 effectively promoted the degradation of full-length HER2 and truncated p95HER2, while also attenuating hetero-dimerization of HER2 family members. The impairment of cancer stem-like traits was observed with reductions in ALDH1 activity, the CD24low/CD44high subpopulation, and mammosphere formation in vitro and in vivo. NCT-547 was an effective inhibitor of tumor growth and angiogenesis, and no toxic outcomes were found in initial hepatic and renal analysis. Our findings suggest that NCT-547 may have applications in addressing trastuzumab resistance in HER2-positive breast cancer.
Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Trastuzumab/farmacología , Animales , Antineoplásicos/química , Antineoplásicos Inmunológicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Femenino , Humanos , Ratones , Células Madre Neoplásicas , Dominios Proteicos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of 1-indazol-3-(1-phenylpyrazol-5-yl)methyl ureas were investigated as hTRPV1 antagonists. The structure-activity relationship study was conducted systematically for both the indazole A-region and the 3-trifluoromethyl/t-butyl pyrazole C-region to optimize the antagonism toward the activation by capsaicin. Among them, the antagonists 26, 50 and 51 displayed highly potent antagonism with Ki(CAP) = 0.4-0.5 nM. Further, in vivo studies in mice indicated that these derivatives both antagonized capsaicin induced hypothermia, consistent with their in vitro activity, and themselves did not induce hyperthermia. In the formalin model, 51 showed anti-nociceptive activity in a dose-dependent manner.
Asunto(s)
Indazoles/farmacología , Compuestos de Metilurea/farmacología , Pirazoles/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Temperatura Corporal/efectos de los fármacos , Células CHO , Capsaicina/farmacología , Cricetulus , Humanos , Indazoles/síntesis química , Compuestos de Metilurea/síntesis química , Ratones , Estructura Molecular , Pirazoles/síntesis química , Relación Estructura-Actividad , Canales Catiónicos TRPV/agonistasRESUMEN
A series of O-substituted analogues of the B,C-ring truncated scaffold of deguelin were designed as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antiproliferative agents against HER2-positive breast cancer. Among the synthesized compounds, compound 80 exhibited significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells, whereas compound 80 did not show any cytotoxicity in normal cells. Compound 80 markedly downregulated the expression of the major client proteins of HSP90 in both cell types, indicating that the cytotoxicity of 80 in breast cancer cells is attributed to the destabilization and inactivation of HSP90 client proteins and that HSP90 inhibition represents a promising strategy to overcome trastuzumab resistance. A molecular docking study of 80 with the homology model of a HSP90 homodimer showed that 80 fit nicely in the C-terminal domain with a higher electrostatic complementary score than that of ATP.
Asunto(s)
Antineoplásicos/química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Rotenona/análogos & derivados , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Sitios de Unión , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Rotenona/química , Rotenona/metabolismo , Rotenona/farmacología , Relación Estructura-ActividadRESUMEN
A series of indane-type acetamide and propanamide analogues were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that indane A-region analogues exhibited better antagonism than did the corresponding 2,3-dihydrobenzofuran and 1,3-benzodioxole surrogates. Among them, antagonist 36 exhibited potent and selective antagonism toward capsaicin for hTRPV1 and mTRPV1. Further, in vivo studies indicated that antagonist 36 showed excellent analgesic activity in both phases of the formalin mouse pain model and inhibited the pain behavior completely at a dose of 1 mg/kg in the 2nd phase.
Asunto(s)
Amidas/química , Indanos/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Acetamidas/química , Acetamidas/metabolismo , Acetamidas/uso terapéutico , Amidas/metabolismo , Amidas/uso terapéutico , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Capsaicina/química , Capsaicina/metabolismo , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Piridinas/química , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
Diacylglycerol (DAG) is a key lipid second messenger downstream of cellular receptors that binds to the C1 domain in many regulatory proteins. Protein kinase C (PKC) isoforms constitute the most prominent family of signaling proteins with DAG-responsive C1 domains, but six other families of proteins, including the chimaerins, Ras-guanyl nucleotide-releasing proteins (RasGRPs), and Munc13 isoforms, also play important roles. Their significant involvement in cancer, immunology, and neurobiology has driven intense interest in the C1 domain as a therapeutic target. As with other classes of targets, however, a key issue is the establishment of selectivity. Here, using [3H]phorbol 12,13-dibutyrate ([3H]PDBu) competition binding assays, we found that a synthetic DAG-lactone, AJH-836, preferentially binds to the novel PKC isoforms PKCδ and PKCϵ relative to classical PKCα and PKCßII. Assessment of intracellular translocation, a hallmark for PKC activation, revealed that AJH-836 treatment stimulated a striking preferential redistribution of PKCϵ to the plasma membrane relative to PKCα. Moreover, unlike with the prototypical phorbol ester phorbol 12-myristate 13-acetate (PMA), prolonged exposure of cells to AJH-836 selectively down-regulated PKCδ and PKCϵ without affecting PKCα expression levels. Biologically, AJH-836 induced major changes in cytoskeletal reorganization in lung cancer cells, as determined by the formation of membrane ruffles, via activation of novel PKCs. We conclude that AJH-836 represents a C1 domain ligand with PKC-activating properties distinct from those of natural DAGs and phorbol esters. Our study supports the feasibility of generating selective C1 domain ligands that promote novel biological response patterns.
Asunto(s)
Diglicéridos/química , Lactonas/metabolismo , Proteína Quinasa C-alfa/metabolismo , Proteína Quinasa C-delta/metabolismo , Proteína Quinasa C-epsilon/metabolismo , Células A549 , Unión Competitiva , Células HeLa , Humanos , Ligandos , Unión Proteica , Transporte de Proteínas , Especificidad por SustratoRESUMEN
Leucyl-tRNA synthetase (LRS) plays an important role in amino acid-dependent mTORC1 signaling, which is known to be associated with cellular metabolism and proliferation. Therefore, LRS-targeting small molecules that can suppress mTORC1 activation may provide an alternative strategy to current anticancer therapy. In this work, we developed a library of leucyladenylate sulfate analogues by extensively modifying three different pharmacophoric regions comprising adenine, ribose and leucine. Several effective compounds were identified by cell-based mTORC1 activation assays and further tested for anticancer activity. The selected compounds mostly exhibited selective cytotoxicity toward five different cancer cell lines, supporting the hypothesis that the LRS-mediated mTORC1 pathway is a promising alternative target to current therapeutic approaches.
Asunto(s)
Leucina-ARNt Ligasa/metabolismo , Leucina/análogos & derivados , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células HEK293 , Humanos , Leucina/química , Leucina/metabolismo , Leucina/farmacología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Rotenona/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Rotenona/síntesis química , Rotenona/química , Rotenona/farmacología , Relación Estructura-ActividadRESUMEN
A series of A-region analogues of 2-(3-fluoro-4-methylsufonamidophenyl) propanamide 1 were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that a fluoro group at the 3- (or/and) 5-position and a methylsulfonamido group at the 4-position were optimal for antagonism of TRPV1 activation by capsaicin. The most potent antagonist 6 not only exhibited potent antagonism of activation of hTRPV1 by capsaicin, low pH and elevated temperature but also displayed highly potent antagonism of activation of rTRPV1 by capsaicin. Further studies demonstrated that antagonist 6 blocked the hypothermic effect of capsaicin in vivo, consistent with its in vitro mechanism, and it showed promising analgesic activity in the formalin animal model.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Canales Catiónicos TRPV/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Animales , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Ratas , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
According to recent studies, leucyl-tRNA synthetase (LRS) acts as a leucine sensor and modulates the activation of the mammalian target of rapamycin complex 1 (mTORC1) activation. Because overactive mTORC1 is associated with several diseases, including colon cancer, LRS-targeted mTORC1 inhibitors represent a potential option for anti-cancer therapy. In this work, we developed a series of simplified leucyladenylate sulfamate analogues that contain the N-(3-chloro-4-fluorophenyl)quinazolin-4-amine moiety to replace the adenine group. We identified several compounds with comparable activity to previously reported inhibitors and exhibited selective mTORC1 inhibition and anti-cancer activity. This study further supports the hypothesis that LRS is a promising target to modulate the mTORC1 pathway.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Leucina-ARNt Ligasa/antagonistas & inhibidores , Leucina/análogos & derivados , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Leucina/síntesis química , Leucina/química , Leucina/farmacología , Leucina-ARNt Ligasa/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 2-(3,5-substituted 4-aminophenyl)acetamide and propanamide derivatives were investigated as human TRPV1 antagonists. The analysis of the structure-activity relationship indicated that 2-(3,5-dihalo 4-aminophenyl)acetamide analogues displayed excellent antagonism of hTRPV1 activation by capsaicin and showed improved potency compared to the corresponding propanamides. The most potent antagonist (36) exhibited potent and selective antagonism for hTRPV1 not only to capsaicin but also to NADA and elevated temperature; however, it only displayed weak antagonism to low pH. Further studies indicated that oral administration of antagonist 36 blocked the hypothermic effect of capsaicin in vivo but demonstrated hyperthermia at that dose. A docking study of 36 was performed in our established hTRPV1 homology model to understand its binding interactions with the receptor and to compare with that of previous antagonist 1.
Asunto(s)
Amidas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Acetamidas/química , Acetamidas/farmacología , Acetamidas/uso terapéutico , Amidas/farmacología , Amidas/uso terapéutico , Sitios de Unión , Capsaicina/química , Capsaicina/toxicidad , Humanos , Concentración de Iones de Hidrógeno , Hipotermia/patología , Hipotermia/prevención & control , Ligandos , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer's disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC50 values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity. Among these, inhibitors 51 and 53 displayed the most potent AßN3pE-40-lowering effects in in vivo acute model with reasonable BBB penetration, without showing cytotoxicity and hERG inhibition. The molecular modeling analysis of 53 indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound 53 may serve as a potential candidate for anti-Alzheimer's agents.