RESUMEN
Pharmacokinetic variability in drug plasma exposure between different studies within the same species is not unexpected due to a variety of factors (such as differences in formulation, active pharmaceutical ingredient salt form and solid-state, genetic strain, sex, environmental, disease status, bioanalysis methods, circadian rhythms, etc.) although variability from within the same research group typically does not occur to a great degree because these variables are commonly controlled. Surprisingly, a pharmacology proof of concept study with a previously validated tool compound from the literature failed to show expected response in murine glucose-6-phosphate isomerase-induced arthritis model which was tied to compound plasma exposure unexpectedly 10-fold lower than exposure observed from early pharmacokinetic study confirming adequate exposure prior to proof of concept. A systematic series of studies were conducted to investigate causes for exposure difference between pharmacology and pharmacokinetic studies identifying the presence or absence of soy protein in animal chow as the causative variable. Cyp3a11 expression in intestine and liver was determined to increase in a time dependent manner in mice switched to diets containing soybean meal compared with mice on diets without soybean meal. The repeated pharmacology experiments using the soybean meal free diet achieved plasma exposures that were maintained above the EC50 and showed efficacy and proof of concept for the target. This effect was further confirmed with marker CYP3A4 substrates in follow on mouse studies. The role of soy protein containing diets on CYP expression necessitates the inclusion of controlling rodent diet as a variable for preventing possible exposure differences between studies. SIGNIFICANCE STATEMENT: The presence of soybean meal protein in murine diet increased clearance and decreased oral exposure for select cytochrome 3A4 substrates. Related effects were also observed on select liver enzyme expression.
Asunto(s)
Dieta , Proteínas de Soja , Ratones , Animales , Proteínas de Soja/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Hígado/metabolismo , IntestinosRESUMEN
A novel series of N-type calcium channel inhibitors have been discovered. Optimization of potency and HT-ADME properties provides 4-aminocyclopentapyrrolidines with analgesic efficacy after oral dosing.
Asunto(s)
Analgésicos/química , Analgésicos/uso terapéutico , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo N/metabolismo , Neuralgia/tratamiento farmacológico , Administración Oral , Analgésicos/síntesis química , Analgésicos/metabolismo , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/metabolismo , Humanos , Microsomas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of diphenyl lactam containing calcium channel blockers is described. Extensive SAR studies resulted in compounds with low molar activity and good plasma exposure after oral dosing. Compounds 2, 6 and 7 demonstrated significant efficacy in the capsaicin model of secondary hyperalgesia following oral administration.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio Tipo N/metabolismo , Descubrimiento de Drogas , Lactamas/síntesis química , Administración Oral , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacocinética , Concentración 50 Inhibidora , Lactamas/química , Lactamas/farmacocinética , Estructura Molecular , Piperazinas/química , Ratas , SolubilidadRESUMEN
A novel 4-aminocyclopentapyrrolidine series of N-type Ca(2+) channel blockers have been discovered. Enantioselective synthesis of the 4-aminocyclopentapyrrolidines was enabled using N-tert-butyl sulfinamide chemistry. SAR studies demonstrate selectivity over L-type Ca(2+) channels. N-type Ca(2+) channel blockade was confirmed using electrophysiological recording techniques. Compound 25 is an N-type Ca(2+) channel blocker that produces antinociception in inflammatory and nociceptive pain models without exhibiting cardiovascular or motor liabilities.
Asunto(s)
Acetamidas/síntesis química , Analgésicos/síntesis química , Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio Tipo N/química , Pirrolidinas/química , Pirrolidinas/síntesis química , Acetamidas/farmacología , Acetamidas/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo N/metabolismo , Modelos Animales de Enfermedad , Masculino , Dolor/tratamiento farmacológico , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Vanilloid receptor TRPV1 is a 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 by several pharmaceutical companies in an effort to identify novel agents for pain management. Here we report that replacement of substituted benzyl groups by an indan rigid moiety in a previously described N-indazole- N'-benzyl urea series led to a number of TRPV1 antagonists with significantly increased in vitro potency and enhanced drug-like properties. Extensive evaluation of pharmacological, pharmacokinetic, and toxicological properties of synthesized analogs resulted in identification of ( R)-7 ( ABT-102). Both the analgesic activity and drug-like properties of ( R)-7 support its advancement into clinical pain trials.
Asunto(s)
Analgésicos/síntesis química , Indazoles/síntesis química , Indenos/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Urea/análogos & derivados , Urea/síntesis química , Administración Oral , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Perros , Haplorrinos , Humanos , Técnicas In Vitro , Indazoles/farmacocinética , Indazoles/farmacología , Indenos/farmacocinética , Indenos/farmacología , Microsomas Hepáticos/metabolismo , Dolor/tratamiento farmacológico , Dolor/etiología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Urea/farmacocinética , Urea/farmacologíaRESUMEN
The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.
Asunto(s)
Analgésicos/síntesis química , Indazoles/síntesis química , Compuestos de Fenilurea/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Urea/análogos & derivados , Administración Oral , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Perros , Estabilidad de Medicamentos , Humanos , Técnicas In Vitro , Indazoles/farmacocinética , Indazoles/farmacología , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Isoquinolinas/farmacología , Microsomas Hepáticos/metabolismo , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Ratas , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacocinética , Urea/farmacologíaRESUMEN
Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H(3) receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H(3) receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H(3) receptors (H(3), K(i)=1.5 nM) versus off-target receptors and channels (including the hERG K(+) channel, K(i)>9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4)=2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP(450) inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9h, 1.7h in dog, 1.8h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.
Asunto(s)
Conducta Animal/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/fisiología , Animales , Conducta Animal/fisiología , Benzofuranos/química , Benzofuranos/farmacología , Perros , Haplorrinos , Antagonistas de los Receptores Histamínicos/sangre , Humanos , Ratas , Receptores Histamínicos H3/efectos de los fármacosRESUMEN
A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.
Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Oximas/farmacología , Piperazinas/farmacología , Receptores de Dopamina D4/agonistas , Animales , Benzamidas/química , Benzamidas/farmacología , Sitios de Unión , Línea Celular , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Hurones , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Oximas/síntesis química , Oximas/química , Piperazinas/síntesis química , Piperazinas/química , Ratas , Ratas Wistar , 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
2-[4-(3,4-Dimethylphenlyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393) was identified as a potent dopamine D4 receptor antagonist with excellent receptor selectivity. [3H]-spiperone competition binding assays showed that A-381393 potently bound to membrane from cells expressing recombinant human dopamine D4.4 receptor (Ki=1.5 nM), which was 20-fold higher than that of clozapine (Ki=30.4 nM). A-381393 exhibited highly selective binding for the dopamine D4.4 receptor (>2700-fold) when compared to D1, D2, D3 and D5 dopamine receptors. Furthermore, in comparison to clozapine and L-745870, A-381393 exhibits better receptor selectivity, showing no affinity up to 10 microM for a panel of more than 70 receptors and channels, with the exception of moderate affinity for 5-HT2A (Ki=370 nM). A-381393 potently inhibited the functional activity of agonist-induced GTP-gamma-S binding assay and 1 microM dopamine induced-Ca2+ flux in human dopamine D4.4 receptor expressing cells, but not in human dopamine D2L or D3 receptor cells. In contrast to L-745870, A-381393 did not exhibit any significant intrinsic activity in a D4.4 receptor. In vivo, A-381393 has good brain penetration after subcutaneous administration. A-381393 inhibited penile erection induced by the selective D4 agonist PD168077 in conscious rats. Thus, A-381393 is a novel selective D4 antagonist that will enhance the ability to study dopamine D4 receptors both in vitro and in vivo.
Asunto(s)
Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Animales , Benzamidas/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Unión Competitiva/efectos de los fármacos , Calcio/metabolismo , Línea Celular , Clozapina/farmacocinética , Dopamina/metabolismo , Antagonistas de Dopamina/química , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Interacciones Farmacológicas , Europio/farmacocinética , Fluorometría/métodos , Antagonistas del GABA/farmacocinética , Guanosina Trifosfato/farmacocinética , Humanos , Masculino , Erección Peniana/efectos de los fármacos , Piperazinas/síntesis química , Piperazinas/farmacocinética , Piperazinas/farmacología , Piridinas/farmacocinética , Pirroles/farmacocinética , Ensayo de Unión Radioligante/métodos , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Espiperona/farmacocinética , Factores de Tiempo , Tritio/farmacocinéticaRESUMEN
A-412997 (2-(3',4',5',6'-tetrahydro-2'H-[2,4'] bipyridinyl-1'-yl)-N-m-tolyl-acetamide) is a highly selective dopamine D4 receptor agonist that binds with high affinity to rat dopamine D4 and human dopamine D4.4 receptors (Ki=12.1 and 7.9 nM, respectively). In contrast to the dopamine D4 receptor agonists PD168077 and CP226269, A-412997 showed a better selectivity profile and no affinity <1000 nM for other dopamine receptors or any other proteins in a panel of seventy different receptors and channels. In functional assays using calcium flux, A-412997 was a potent full agonist at rat dopamine D4 receptors (28.4 nM, intrinsic activity=0.83) and did not activate rat dopamine D2L receptors, unlike CP226269. Dopamine D4 receptor selective agonists have been shown to induce penile erection in rats by central mechanisms. A-412997 induces penile erection in a conscious rat model (effective dose=0.1 micromol/kg, s.c.) with comparable efficacy as the nonselective D2-like agonist, apomorphine. When dosed systemically, A-412997 crossed the blood brain barrier rapidly and achieved significantly higher levels than PD168077. A-412997 is a highly selective dopamine D4 receptor agonist and a useful tool to understand the role of dopamine D4 receptors in rat models of central nervous system processes and disease.
Asunto(s)
Acetamidas/farmacología , Agonistas de Dopamina/farmacología , Piridinas/farmacología , Receptores de Dopamina D4/agonistas , Acetamidas/farmacocinética , Animales , Línea Celular , Agonistas de Dopamina/farmacocinética , Humanos , Masculino , Erección Peniana/efectos de los fármacos , Piridinas/farmacocinética , Ratas , Ratas WistarRESUMEN
Environmental enrichment in rodents may improve animal well-being but can affect neurologic development, immune system function, and aging. We tested the hypothesis that wood block enrichment affects the interpretation of traditional and transcriptomic endpoints in an exploratory toxicology testing model using a well-characterized reference compound, cyclophosphamide. ANOVA was performed to distinguish effects of wood block enrichment separate from effects of 40 mg/kg cyclophosphamide treatment. Biologically relevant and statistically significant effects of wood block enrichment occurred only for body weight gain. ANOVA demonstrated the expected effects of cyclophosphamide on food consumption, spleen weight, and hematology. According to transcriptomic endpoints, cyclophosphamide induced fewer changes in gene expression in liver than in spleen. Splenic transcriptomic pathways affected by cyclophosphamide included: iron hemostasis; vascular tissue angiotensin system; hepatic stellate cell activation and fibrosis; complement activation; TGFß-induced hypertrophy and fibrosis; monocytes, macrophages, and atherosclerosis; and platelet activation. Changes in these pathways due to cyclophosphamide treatment were consistent with bone marrow toxicity regardless of enrichment. In a second study, neither enrichment nor type of cage flooring altered body weight or food consumption over a 28-d period after the first week. In conclusion, wood block enrichment did not interfere with a typical exploratory toxicology study; the effects of ingested wood on drug level kinetics may require further consideration.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Ciclofosfamida/administración & dosificación , Ratas , Toxicología/métodos , Administración Oral , Animales , Animales de Laboratorio , Peso Corporal/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , MaderaRESUMEN
The histamine H(3) receptor is predominantly expressed in the central nervous system and plays a role in diverse physiological mechanisms. In the present study, the effects of GSK189254, a potent and selective H(3) antagonist, were characterized in preclinical pain models in rats. Systemic GSK189254 produced dose-dependent efficacy (ED(50)=0.77 mg/kg i.p.) in a rat model of monoiodoacetate (MIA) induced osteoarthritic (OA) pain as evaluated by hindlimb grip force. The role of H(3) receptors in regulating pain perception was further demonstrated using other structurally distinct H(3) antagonists. GSK189254 also displayed efficacy in a rat surrogate model indicative of central sensitization, namely phase 2 response of formalin-induced flinching, and attenuated tactile allodynia in the spinal nerve ligation model of neuropathic pain (ED(50)=1.5mg/kg i.p.). In addition, GSK189254 reversed persistent (CFA) (ED(50)=2.1mg/kg i.p,), whereas was ineffective in acute (carrageenan) inflammatory pain. When administered intrathecally (i.t.) to the lumbar spinal cord, GSK189254 produced robust effects in relieving the OA pain (ED(50)=0.0027 mg/kg i.t.). The systemic GSK189254 effect was completely reversed by the alpha-adrenergic receptor antagonist phentolamine (i.p. and i.t.) but not by the opioid receptor antagonist naloxone (i.p.). Furthermore, the i.t. GSK189254 effect was abolished when co-administered with phentolamine (i.t.). These results suggest that the spinal cord is an important site of action for H(3) antagonism and the effect can be associated with activation of the noradrenergic system. Our data also provide support that selective H(3) antagonists may represent a class of agents for the treatment of pain disorders.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/farmacología , Neuronas/efectos de los fármacos , Norepinefrina/metabolismo , Dimensión del Dolor/efectos de los fármacos , Dolor/tratamiento farmacológico , Receptores Histamínicos H3/metabolismo , Antagonistas Adrenérgicos alfa/farmacología , Análisis de Varianza , Animales , Benzazepinas/farmacología , Relación Dosis-Respuesta a Droga , Formaldehído , Fuerza de la Mano , Inyecciones Espinales , Masculino , Actividad Motora/efectos de los fármacos , Neuronas/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacología , Dolor/inducido químicamente , Dolor/metabolismo , Percepción del Dolor/efectos de los fármacos , Fentolamina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
A series of compounds was designed as dual inhibitors of the H(3) receptor and the norepinephrine transporter. Compound 5 (rNET K(i) = 14 nM; rH(3)R K(i) = 37 nM) was found to be efficacious in a rat model of osteoarthritic pain.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/síntesis química , Naftoles/síntesis química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Dolor/tratamiento farmacológico , Pirrolidinas/síntesis química , Animales , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Antagonistas de los Receptores Histamínicos H3/farmacología , Naftoles/farmacocinética , Naftoles/farmacología , Osteoartritis/tratamiento farmacológico , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The histamine H(4) receptor (H(4)R) is expressed primarily on cells involved in inflammation and immune responses. To determine the potential role of H(4)R in pain transmission, the effects of JNJ7777120, a potent and selective H(4) antagonist, were characterized in preclinical pain models. Administration of JNJ7777120 fully blocked neutrophil influx observed in a mouse zymosan-induced peritonitis model (ED(50)=17 mg/kg s.c., 95% CI=8.5-26) in a mast cell-dependent manner. JNJ7777120 potently reversed thermal hyperalgesia observed following intraplantar carrageenan injection of acute inflammatory pain (ED(50)=22 mg/kg i.p., 95% CI=10-35) in rats and significantly decreased the myeloperoxide activity in the carrageenan-injected paw. In contrast, no effects were produced by either H(1)R antagonist diphenhydramine, H(2)R antagonists ranitidine, or H(3)R antagonist ABT-239. JNJ7777120 also exhibited robust anti-nociceptive activity in persistent inflammatory (CFA) pain with an ED(50) of 29 mg/kg i.p. (95% CI=19-40) and effectively reversed monoiodoacetate (MIA)-induced osteoarthritic joint pain. This compound also produced dose-dependent anti-allodynic effects in the spinal nerve ligation (ED(50)=60 mg/kg) and sciatic nerve constriction injury (ED(50)=88 mg/kg) models of chronic neuropathic pain, as well as in a skin-incision model of acute post-operative pain (ED(50)=68 mg/kg). In addition, the analgesic effects of JNJ7777120 were maintained following repeated administration and were evident at the doses that did not cause neurologic deficits in rotarod test. Our results demonstrate that selective blockade of H(4) receptors in vivo produces significant anti-nociception in animal models of inflammatory and neuropathic pain.
Asunto(s)
Analgésicos/farmacología , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Analgésicos/uso terapéutico , Animales , Masculino , Ratones , Ratones Endogámicos BALB C , Ensayo de Unión Radioligante , Ratas , Receptores Histamínicos , Receptores Histamínicos H4RESUMEN
A new structural class of histamine H 4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4 antagonists, functional H 4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H 4 pharmacology. It is a potent H 4 antagonist in functional assays across species (FLIPR Ca (2+) flux, K b < 5.7 nM), has high (>190x) selectivity for H 4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50 = 37 micromol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50 = 72 micromol/kg, rat).
Asunto(s)
Aminas/química , Antiinflamatorios/síntesis química , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/uso terapéutico , Dolor/tratamiento farmacológico , Pirimidinas/síntesis química , Receptores Histamínicos/metabolismo , Animales , Antiinflamatorios/química , Antiinflamatorios/clasificación , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/clasificación , Ligandos , Ratones , Estructura Molecular , Pirimidinas/química , Pirimidinas/clasificación , Pirimidinas/uso terapéutico , RatasRESUMEN
A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4- tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6- tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H 4R antagonists in pain.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptores Histamínicos/metabolismo , Animales , Biomarcadores , Antagonistas de los Receptores Histamínicos/química , Humanos , Hiperplasia/inducido químicamente , Hiperplasia/prevención & control , Ligandos , Locomoción/efectos de los fármacos , Ratones , Estructura Molecular , Pirimidinas/química , Ratas , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Benzofuranos/farmacología , Hiperalgesia/tratamiento farmacológico , Dolor/prevención & control , Quinazolinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Benzofuranos/síntesis química , Benzofuranos/química , Carragenina , Modelos Animales de Enfermedad , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Hiperalgesia/inducido químicamente , Ligandos , Ratones , Estructura Molecular , Dolor/fisiopatología , Peritonitis/tratamiento farmacológico , Quinazolinas/síntesis química , Quinazolinas/química , Ratas , Receptores Histamínicos , Receptores Histamínicos H4 , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
SAR studies for N-aryl-N'-benzyl urea class of TRPV1 antagonists have been extended to cover alpha-benzyl alkylation. Alkylated compounds showed weaker in vitro potencies in blocking capsaicin activation of TRPV1 receptor, but possessed improved pharmacokinetic properties. Further structural manipulations that included replacement of isoquinoline core with indazole and isolation of single enantiomer led to TRPV1 antagonists like (R)-16a with superior pharmacokinetic properties and greater potency in animal model of inflammatory pain.
Asunto(s)
Analgésicos/farmacología , Inflamación/tratamiento farmacológico , Modelos Biológicos , Dolor/tratamiento farmacológico , Canales Catiónicos TRPV/antagonistas & inhibidores , Urea/farmacología , Analgésicos/farmacocinética , Analgésicos/uso terapéutico , Animales , Metilación , Ratas , Urea/farmacocinética , Urea/uso terapéuticoRESUMEN
Novel 5,6-fused heteroaromatic ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that 4-aminoindoles and indazoles are the preferential cores for the attachment of ureas. Bulky electron-withdrawing groups in the para-position of the aromatic ring of the urea substituents imparted the best in vitro potency at TRPV1. The most potent derivatives were assessed in in vivo inflammatory and neuropathic pain models. Compound 46, containing the indazole core and a 3,4-dichlorophenyl group appended to it via a urea linker, demonstrated in vivo analgesic activity upon oral administration. This derivative also showed selectivity versus other receptors in the CEREP screen and exhibited acceptable cardiovascular safety at levels exceeding the therapeutic dose.