RESUMEN
The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.
Asunto(s)
Isoquinolinas/farmacología , Pirazinas/farmacología , Receptor de Serotonina 5-HT2C/metabolismo , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Modelos Moleculares , Estructura Molecular , Pirazinas/síntesis química , Pirazinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Synthesis and structure-activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors.
Asunto(s)
Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Piperidinas/química , Pirrolidinas/química , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Unión Proteica , Pirrolidinas/síntesis química , Pirrolidinas/metabolismo , Relación Estructura-Actividad , TemperaturaRESUMEN
The synthesis and structure-activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with beta-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold.
Asunto(s)
Dipéptidos/química , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de la Dipeptidil-Peptidasa IV/química , Dipéptidos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Evaluación Preclínica de Medicamentos , Humanos , Nitrilos/química , Nitrilos/farmacología , Relación Estructura-ActividadRESUMEN
The serine protease tryptase has been associated with a broad range of allergic and inflammatory diseases and, in particular, has been implicated as a critical mediator of asthma. The inhibition of tryptase therefore has the potential to be a valuable therapy for asthma. The synthesis, employing solution phase parallel methods, and SAR of a series of novel 2-azepanone tryptase inhibitors are presented. A member of this series, 8t, was identified as a potent inhibitor of human tryptase (IC(50)=38 nM) with selectivity >/=330-fold versus related serine proteases (trypsin, plasmin, uPA, tPA, APC, alpha-thrombin, and FXa) [corrected].
Asunto(s)
Azepinas/síntesis química , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/síntesis química , Azepinas/farmacología , Humanos , Inhibidores de Serina Proteinasa/farmacología , TriptasasRESUMEN
In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Fenilbutiratos/farmacología , Fenilbutiratos/farmacocinética , Acetatos/química , Administración Oral , Aminopiridinas/química , Animales , Disponibilidad Biológica , Adhesión Celular/efectos de los fármacos , Línea Celular , Semivida , Humanos , Fenilbutiratos/química , RatasRESUMEN
Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.