RESUMEN
A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.
Asunto(s)
Compuestos de Anilina/química , Benzamidas/química , Receptor Cannabinoide CB2/agonistas , Sulfonamidas/química , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacocinética , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Dolor/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB2 ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB2 agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.
Asunto(s)
Aminopiridinas/química , Morfolinas/química , Piridinas/química , Receptor Cannabinoide CB2/agonistas , Administración Oral , Aminopiridinas/síntesis química , Aminopiridinas/farmacología , Animales , Perros , Humanos , Masculino , Microsomas Hepáticos , Morfolinas/síntesis química , Morfolinas/farmacología , Dolor/tratamiento farmacológico , Unión Proteica , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB(2) agonists. Selective CB(2) agonist 31 (K(i)=2.7; CB(1)/CB(2)=190) displayed robust activity in a rodent model of postoperative pain.
Asunto(s)
Antiinflamatorios/química , Benzamidas/química , Receptor Cannabinoide CB2/agonistas , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Células CHO , Línea Celular , Cricetinae , Cricetulus , Descubrimiento de Drogas , Humanos , Dolor Postoperatorio/tratamiento farmacológico , Ratas , Receptor Cannabinoide CB2/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , TransfecciónRESUMEN
Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
Asunto(s)
Analgésicos/farmacología , Analgésicos/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Dolor/tratamiento farmacológico , Receptores Opioides delta/agonistas , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Benzopiranos/administración & dosificación , Benzopiranos/química , Células CHO , Ensayos Clínicos como Asunto , Cricetinae , Cricetulus , Cristalografía por Rayos X , Inhibidores del Citocromo P-450 CYP2D6 , Perros , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Hiperalgesia/tratamiento farmacológico , Masculino , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/químicaRESUMEN
Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally. Efficacy after oral administration was observed only when ABT, a cytochrome P450 suicide inhibitor, was coadministered.
Asunto(s)
Benzamidas/farmacología , Receptor Cannabinoide CB2/efectos de los fármacos , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Benzamidas/uso terapéutico , Dolor/tratamiento farmacológico , RoedoresRESUMEN
Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.
Asunto(s)
Analgésicos/administración & dosificación , Benzamidas/administración & dosificación , Benzopiranos/administración & dosificación , Dolor/tratamiento farmacológico , Receptores Opioides delta/agonistas , Administración Oral , Analgésicos/síntesis química , Analgésicos/química , Animales , Benzamidas/síntesis química , Benzamidas/química , Benzopiranos/síntesis química , Benzopiranos/química , Disponibilidad Biológica , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Humanos , Dosis Máxima Tolerada , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Ratas , Pruebas de ToxicidadRESUMEN
N-in-1 (or cassette) dosing pharmacokinetics (PK) has been used in drug discovery for rapid assessment of PK properties of new chemical entities. However, because of potential for drug-drug interactions this procedure is still controversial. This study was to retrospectively evaluate the N-in-1 dosing approach in drug discovery with an emphasis on the potential for drug-drug interactions. The systemic clearance, volume of distribution, oral bioavailability, and renal excretion of the 31 lead compounds in rats, dogs or chimpanzees were significantly correlated between the N-in-1 dosing and discrete studies with r values of 0.69, 0.91, 0.53, and 0.83 (p < 0.005 for all), respectively. PK parameters for 11 quality control compounds which were involved in 194 N-in-1 studies for screening approximately 1000 compounds had coefficient of variations of less than 70%. The intrinsic microsomal clearances generated from the N-in-1 and discrete incubations were nearly identical (r = 0.97, p < 0.0001). The intrinsic clearances of quality control compound from the N-in-1 incubations were consistent with its discrete CL(int) estimate (cv: 5.4%). Therefore, N-in-1 dosing is a useful approach in drug discovery to quickly obtain initial PK estimates. Potential drug-drug interactions that result in confounding PK estimates do not occur as frequently as expected.
Asunto(s)
Inhibidores del Citocromo P-450 CYP3A , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Microsomas Hepáticos , Preparaciones Farmacéuticas/administración & dosificación , Farmacocinética , Animales , Disponibilidad Biológica , Citocromo P-450 CYP3A , Perros , Interacciones Farmacológicas , Humanos , Técnicas In Vitro , Masculino , Tasa de Depuración Metabólica , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Modelos Biológicos , Pan troglodytes , RatasRESUMEN
DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)) is a potent and selective inhibitor of tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF-alpha production in blood from rodents, chimpanzee, and human, with IC(50) values ranging from 17 to 100 nM. In rodent models of endotoxemia, DPC 333 inhibited the production of TNF-alpha in a dose-dependent manner, with an oral ED(50) ranging from 1.1 to 6.1 mg/kg. Oral dosing of DPC 333 at 5.5 mg/kg daily for 2 weeks in a rat collagen antibody-induced arthritis model suppressed the maximal response by approximately 50%. DPC 333 was distributed widely to tissues including the synovium, the site of action for antiarthritic drugs. Pharmacokinetic and pharmacodynamic studies in chimpanzee revealed a systemic clearance of 0.4 l/h/kg, a V(ss) of 0.6 l/kg, an oral bioavailability of 17%, and an ex vivo IC(50) for the suppression of TNF-alpha production of 55 nM (n = 1). In a phase I clinical trial with male volunteers after single escalating doses of oral DPC 333, the terminal half-life was between 3 and 6 h and the ex vivo IC(50) for suppressing TNF-alpha production was 113 nM. Measurement of the suppression of TNF-alpha production ex vivo may serve as a good biomarker in evaluating the therapeutic efficacy of TACE inhibitors. Overall, the pharmacological profiles of DPC 333 support the notion that suppression of TNF-alpha with TACE inhibitors like DPC 333 may provide a novel approach in the treatment of various inflammatory diseases including rheumatoid arthritis, via control of excessive TNF-alpha production.