RESUMEN
GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.
Asunto(s)
Compuestos Aza/química , Inhibidores Enzimáticos/química , Quinolinas/química , Animales , Sitios de Unión , Encéfalo/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Estabilidad de Medicamentos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Oxidorreductasas Intramoleculares/metabolismo , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación de Dinámica Molecular , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 4 antagonized capsaicin-induced Ca(2+) influx, with an IC50 value of 4.6 nM. In the complete Freund's adjuvant- and carrageenan-induced thermal hypersensitivity models, 4 exhibited full efficacy, with ED80 values of 7.8 and 0.5 mg/kg, respectively, corresponding to plasma levels of 270.8 and 9.2 ng/mL, respectively. On the basis of its superior pharmacologic and safety profile, 4 (mavatrep) was selected for clinical development for the treatment of pain.
Asunto(s)
Analgésicos/química , Bencimidazoles/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Disponibilidad Biológica , Carragenina , Perros , Adyuvante de Freund , Células HEK293 , Haplorrinos , Calor , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A series of arylglycine-based analogs was synthesized and tested for TRPM8 antagonism in a cell-based functional assay. Following structure-activity relationship studies in vitro, a number of compounds were identified as potent TRPM8 antagonists and were subsequently evaluated in an in vivo pharmacodynamic assay of icilin-induced 'wet-dog' shaking in which compound 12 was fully effective. TRPM8 antagonists of the type described here may be useful in treating pain conditions wherein cold hypersensitivity is a dominant feature.
Asunto(s)
Glicina/farmacología , Canales Catiónicos TRPM/antagonistas & inhibidores , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glicina/análogos & derivados , Glicina/química , Células HEK293 , Humanos , Estructura Molecular , Pirimidinonas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Canales Catiónicos TRPM/agonistasRESUMEN
A series of benzothiophene-based phosphonates was synthesized and many analogs within the series were shown to be potent antagonists of the TRPM8 channel. The compounds were obtained as a racemic mixture in 5 synthetic steps, and were tested for TRPM8 antagonist activity in a recombinant, canine TRPM8-expressing cell line using a fluorometric imaging plate reader (FLIPR) assay. Structure-activity relationships were developed initially by modification of the core structure and subsequently by variation of the aromatic substituents and the phosphonate ester. Compound 9l was administered intraperitoneally to rats and demonstrated engagement of the TRPM8 target in both prevention and reversal-modes in an icilin-induced 'wet-dog' shake model.
Asunto(s)
Diseño de Fármacos , Organofosfonatos/síntesis química , Canales Catiónicos TRPM/antagonistas & inhibidores , Animales , Línea Celular , Cromatografía Líquida de Alta Presión , Perros , Concentración 50 Inhibidora , Estructura Molecular , Organofosfonatos/química , Organofosfonatos/farmacología , Unión Proteica/efectos de los fármacos , Ratas , Relación Estructura-ActividadRESUMEN
High throughput screening of our compound library revealed a series of N-pyridyl-3-benzamides as low micromolar agonists of the human TRPV1 receptor. Synthesis of analogs in this series led to the discovery of a series of N-quinolin-3-yl-benzamides as low nanomolar antagonists of human TRPV1.
Asunto(s)
Benzamidas/síntesis química , Benzamidas/farmacología , Isoquinolinas/química , Piridinas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Animales , Benzamidas/química , Benzamidas/uso terapéutico , Reactivos de Enlaces Cruzados/química , Humanos , Hiperalgesia/tratamiento farmacológico , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
We report on a series of alpha-substituted-beta-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.
Asunto(s)
Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Tetrahidronaftalenos/farmacología , Urea/farmacología , Unión Competitiva/efectos de los fármacos , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Relación Estructura-Actividad , Canales Catiónicos TRPV/química , Tetrahidronaftalenos/química , Urea/análogos & derivados , Urea/químicaRESUMEN
Starting from a low micromolar agonist lead identified by high-throughput screening, series of N-isoquinolin-5-yl-N'-aralkyl ureas and analogous amides were developed as potent antagonists of human vanilloid receptor 1 (VR1). The synthesis and structure-activity relationships (SAR) of the series are described.
Asunto(s)
Amidas/química , Isoquinolinas/química , Receptores de Droga/antagonistas & inhibidores , Urea/química , Amidas/metabolismo , Línea Celular , Humanos , Isoquinolinas/metabolismo , Receptores de Droga/metabolismo , Canales Catiónicos TRPV , Urea/metabolismoRESUMEN
Through SAR studies of a piperidinylindoline cinnamide HTS lead, the first potent, non-peptide, low molecular weight selective Neuropeptide Y Y2 (NPY Y2) antagonists have been synthesized. The SAR studies around the piperidinyl, the indolinyl, and the cinnamyl moieties are discussed.
Asunto(s)
Piperidinas/química , Receptores de Neuropéptido Y/antagonistas & inhibidores , Humanos , Piperidinas/metabolismo , Piperidinas/farmacología , Unión Proteica , Receptores de Neuropéptido Y/metabolismoRESUMEN
The design and synthesis of novel pyrrolidine-containing bradykinin antagonists, II, are described. Conformational analysis suggested that a pyrrolidine moiety could substitute for the N-methyl cis-amide moiety of FR 173657. The in vitro binding data showed that the (S)-isomer of II was potent in the bradykinin B(2) receptor-binding assay with a K(i) of 33 nM. The opposite isomer, (R)-II, had a K(i) of 46 nM. The in vitro binding data confirmed our conformational hypothesis.
Asunto(s)
Bradiquinina/antagonistas & inhibidores , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Diseño de Fármacos , Isomerismo , Modelos Moleculares , Conformación Molecular , Receptores de Bradiquinina/metabolismoRESUMEN
The synthesis and structure-activity relationships of a novel series of aroylpyrrole alkylamides as potent selective bradykinin B(2) receptor antagonists are described. Several members of this series display nanomolar affinity at the B(2) receptor and show activity in an animal model of antinociception.