RESUMEN
The voltage-gated sodium channel Nav1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Nav1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Nav1.7 blockers with oral activity, improved selectivity, good drug-like properties, and safety led to the discovery of 2-substituted quinolines and quinolones as potent small molecule Nav1.7 blockers. The design of these molecules focused on maintaining potency at Nav1.7, improving selectivity over the hERG channel, and overcoming phospholipidosis observed with the initial leads. The structure-activity relationship (SAR) studies leading to the discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) are described herein. ABBV-318 displayed robust in vivo efficacy in both inflammatory and neuropathic rodent models of pain. ABBV-318 also inhibited Nav1.8, another sodium channel isoform that is an active target for the development of new pain treatments.
Asunto(s)
Dolor , Canales de Sodio , Humanos , Dolor/tratamiento farmacológico , Manejo del Dolor , Isoformas de Proteínas , Canales de Sodio/metabolismo , Relación Estructura-ActividadRESUMEN
SAR studies on a series of thiophene amide derivatives provided CB(2) receptor agonists. The activity of the compounds was characterized by radioligand binding determination, multiple functional assays, ADME, and pharmacokinetic studies. A representative compound with selectivity for CB(2) over CB(1) effectively produced analgesia in behavioral models of neuropathic, inflammatory, and postsurgical pain. Control experiments using a CB(2) antagonist demonstrated the efficacy in the pain models resulted from CB(2) agonism.
Asunto(s)
Amidas/síntesis química , Analgésicos/síntesis química , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Receptor Cannabinoide CB2/agonistas , Tiofenos/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacologíaRESUMEN
A series of potent indol-3-yl-tetramethylcyclopropyl ketones have been prepared as CB 2 cannabinoid receptor ligands. Two unsubstituted indoles ( 5, 32) were the starting points for an investigation of the effect of indole ring substitutions on CB 2 and CB 1 binding affinities and activity in a CB 2 in vitro functional assay. Indole ring substitutions had varying effects on CB 2 and CB 1 binding, but were generally detrimental to agonist activity. Substitution on the indole ring did lead to improved CB 2/CB 1 binding selectivity in some cases (i.e., 7- 9, 15- 20). All indoles with the morpholino-ethyl side chain ( 32- 43) exhibited weaker binding affinity and less agonist activity relative to that of their tetrahydropyranyl-methyl analogs ( 5- 31). Several agonists were active in the complete Freund's adjuvant model of chronic inflammatory thermal hyperalgesia ( 32, 15).
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Indoles/farmacología , Cetonas/farmacología , Receptor Cannabinoide CB2/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Unión Competitiva , Línea Celular , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Indoles/síntesis química , Indoles/química , Cetonas/síntesis química , Cetonas/química , Ligandos , Conformación Molecular , Ratas , Receptor Cannabinoide CB1/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
Asunto(s)
Benzamidas/síntesis química , Óxidos N-Cíclicos/síntesis química , Disfunción Eréctil/tratamiento farmacológico , Receptores de Dopamina D4/agonistas , Potenciales de Acción , Administración Oral , Animales , Benzamidas/química , Benzamidas/farmacología , Disponibilidad Biológica , Línea Celular , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacología , Perros , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/fisiología , Haplorrinos , Humanos , Técnicas In Vitro , Masculino , Técnicas de Placa-Clamp , Ramos Subendocárdicos/efectos de los fármacos , Ramos Subendocárdicos/fisiología , Ratas , Relación Estructura-ActividadRESUMEN
The genetic validation for the role of the Nav1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog 7 which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, 27 and 48, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both 27 and 48 demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of 48 showed a shift to a lower EC50 over 7 days.
Asunto(s)
Analgésicos/farmacología , Imidazolidinas/farmacología , Indazoles/farmacología , Canal de Sodio Activado por Voltaje NAV1.7/química , Osteoartritis/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pirroles/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Analgésicos/química , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Electrofisiología , Potenciales Evocados , Imidazolidinas/química , Indazoles/química , Ácido Yodoacético/toxicidad , Estructura Molecular , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Osteoartritis/inducido químicamente , Osteoartritis/metabolismo , Dolor/metabolismo , Dolor/patología , Dimensión del Dolor , Pirroles/química , Ratas , Bloqueadores de los Canales de Sodio/química , Relación Estructura-ActividadRESUMEN
SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models.
Asunto(s)
Analgésicos/síntesis química , Compuestos Aza/síntesis química , Fluorenos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Analgésicos/química , Analgésicos/farmacología , Animales , Compuestos Aza/química , Compuestos Aza/farmacología , Calcio/metabolismo , Línea Celular , Cerebelo/metabolismo , Fluorenos/química , Fluorenos/farmacología , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Masculino , Dimensión del Dolor , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
The goal of this study was to develop a new approach to study the pharmacology of the dopamine D(4) receptor that could be used in comparative studies with dopamine D(2) and D(3) receptors. Stable HEK-293 cell lines co-expressing recombinant human D(2L), D(3) or D(4) receptors along with Galpha(qo5) cDNA were prepared. Dopamine induced a robust, transient calcium signal in these cell lines with EC(50)s for D(2L), D(3) and D(4) of 18.0, 11.9 and 2.2 nM, respectively. Reported D(4)-selective agonists CP226269 and PD168077 were potent, partial D(4) agonists exhibiting 31-1700-fold selectivity for D(4) over D(3) or D(2). Non-selective D(2)-like agonists apomorphine and quinpirole showed full efficacy but did not discriminate across the three receptors. D(3)-selective agonists 7-hydroxy-DPAT and PD128907 were potent but non-selective D(2)-like agonists. The reported D(3) partial agonist BP-897 exhibited minimal agonist activity at D(3) but was a potent D(3) antagonist and a partial D(4) agonist. Other D(2)-like antagonists, haloperidol, clozapine, and domperidone showed concentration-dependent inhibition of dopamine responses at all three receptors with K(i) ranging from 0.05 to 48.3 nM. The D(3) selective antagonist S33084 and D(4)-selective antagonist L-745870 were highly selective for D(3) and D(4) receptors with K(b) of 0.7 and 0.1 nM, respectively. Stable co-expression of D(2)-like receptors with chimeric Galpha(qo5) proteins in HEK-293 cells is an efficient method to study receptor activation in a common cellular background and an efficient method for direct comparison of ligand affinity and efficacy across human D(2L), D(3) and D(4) receptors.
Asunto(s)
Calcio/metabolismo , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Receptores de Dopamina D2/metabolismo , Animales , Transporte Biológico , Células CHO , Línea Celular , Células Cultivadas , Cricetinae , Dopamina , Humanos , Receptores de Dopamina D3 , Receptores de Dopamina D4 , Proteínas Recombinantes de Fusión/metabolismoRESUMEN
The behavioral effects evoked by cannabinoids are primarily mediated by the CB(1) and CB(2) cannabinoid receptor subtypes. In vitro pharmacology of cannabinoid receptors has been elucidated using recombinant expression systems expressing either CB(1) or CB(2) receptors, with limited characterization in native cell lines endogenously expressing both CB(1) and CB(2) receptors. In the current study, we report the molecular and pharmacological characterization of the F-11 cell line, a hybridoma of rat dorsal root ganglion neurons and mouse neuroblastoma (N18TG2) cells, reported to endogenously express both cannabinoid receptors. The present study revealed that both receptors are of mouse origin in F-11 cells, and describes the relative gene expression levels between the two receptors. Pharmacological characterization of the F-11 cell line using cannabinoid agonists and antagonists indicated that the functional responses to these cannabinoid ligands are mainly mediated by CB(1) receptors. The non-selective cannabinoid ligands CP 55,940 and WIN 55212-2 are potent agonists and their efficacies in adenylate cyclase and MAPK assays are inhibited by the CB(1) selective antagonist SR141716A (SR1), but not by the CB(2) selective antagonist SR144528 (SR2). The endocannabinoid ligand 2AG, although not active in adenylate cyclase assays, was a potent activator of MAPK signaling in F-11 cells. The analysis of CB(1) and CB(2) receptor gene expression and the characterization of cannabinoid receptor pharmacology in the F-11 cell line demonstrate that it can be used as a tool for interrogating the endogenous signal transduction of cannabinoid receptor subtypes.
Asunto(s)
Línea Celular/efectos de los fármacos , Línea Celular/metabolismo , Ganglios Espinales/citología , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB2/genética , Adenilil Ciclasas/metabolismo , Animales , Secuencia de Bases , Activación Enzimática/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Dosificación de Gen/genética , Expresión Génica/efectos de los fármacos , Humanos , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Datos de Secuencia Molecular , ARN Mensajero/genética , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Especificidad de la EspecieRESUMEN
Several 3-acylindoles with high affinity for the CB(2) cannabinoid receptor and selectivity over the CB(1) receptor have been prepared. A variety of 3-acyl substituents were investigated, and the tetramethylcyclopropyl group was found to lead to high affinity CB(2) agonists (5, 16). Substitution at the N1-indole position was then examined. A series of aminoalkylindoles was prepared and several substituted aminoethyl derivatives were active (23-27, 5) at the CB(2) receptor. A study of N1 nonaromatic side chain variants provided potent agonists at the CB(2) receptor (16, 35-41, 44-47, 49-54, and 57-58). Several polar side chains (alcohols, oxazolidinone) were well-tolerated for CB(2) receptor activity (41, 50), while others (amide, acid) led to weaker or inactive compounds (55 and 56). N1 aromatic side chains also afforded several high affinity CB(2) receptor agonists (61, 63, 65, and 69) but were generally less potent in an in vitro CB(2) functional assay than were nonaromatic side chain analogues.
Asunto(s)
Indoles/farmacología , Cetonas/farmacología , Receptor Cannabinoide CB2/agonistas , Diseño de Fármacos , Humanos , Indoles/síntesis química , Indoles/química , Cetonas/síntesis química , Cetonas/química , Ligandos , Estructura Molecular , Receptor Cannabinoide CB1/agonistas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
High-throughput screening (HTS) identified benzothiazole analogue 3 as a potent fatty acid amide hydrolase (FAAH) inhibitor. Structure-activity relationship (SAR) studies indicated that the sulfonyl group, the piperidine ring and benzothiazole were the key components to their activity, with 16j being the most potent analogue in this series. Time-dependent preincubation study of compound 3 was consistent with it being a reversible inhibitor. Activity-based protein-profiling (ABPP) evaluation of 3 in rat tissues revealed that it had exceptional selectivity and no off-target activity with respect to other serine hydrolases. Molecular shape overlay of 3 with a known FAAH inhibitor indicated that these compounds might act as transition-state analogues, forming putative hydrogen bonds with catalytic residues and mimicking the charge distribution of the tetrahedral transition state. The modeling study also indicated that hydrophobic interactions of the benzothiazole ring with the enzyme contributed to its extraordinary potency. These compounds may provide useful tools for the study of FAAH and the endocannabinoid system.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Benzotiazoles/síntesis química , Benzotiazoles/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Amidohidrolasas/metabolismo , Animales , Benzotiazoles/química , Cristalografía por Rayos X , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Especificidad de Órganos/efectos de los fármacos , Unión Proteica , Ratas , Relación Estructura-Actividad , Factores de TiempoRESUMEN
Our HTS effort yielded a preferential mGluR1 pyrimidinone antagonist 1 with lead-like characteristics. Rapid hit to lead (HTL) study identified compounds with improved functional activity and selectivity such as 1b with little improvements in ADME properties. Addition of an aminosulfonyl group on the N-1 aromatic ring led to 2f, a compound with similar in vitro biochemical profiles as those of 1b but drastically improved in vitro ADME properties. These improvements were paralleled by rat PK study characterized by low clearance and quantitative bioavailability. Compound 2f represented a true lead-like molecule that is amenable for further lead optimization (LO) evaluation.
Asunto(s)
Pirazoles/química , Piridinas/química , Pirimidinonas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Evaluación Preclínica de Medicamentos , Pirimidinonas/química , Pirimidinonas/farmacocinética , RatasRESUMEN
We have discovered a novel, potent, and selective triazafluorenone series of metabotropic glutamate receptor 1 (mGluR1) antagonists with efficacy in various rat pain models. Pharmacokinetic and pharmacodynamic profiles of these triazafluorenone analogs revealed that brain/plasma ratios of these mGluR1 antagonists were important to achieve efficacy in neuropathic pain models. This correlation could be used to guide our in vivo SAR (structure-activity relationship) modification. For example, compound 4a has a brain/plasma ratio of 0.34, demonstrating only moderate efficacy in neuropathic pain models. On the other hand, antagonist 4b with a brain/plasma ratio of 2.70 was fully efficacious in neuropathic pain models.