RESUMEN
6,7-Dihydro-5H-2,1-benzisoxazol-4-one analogs are potent inhibitors of aldosterone synthase (CYP11B2) with selectivity over the highly homologous enzyme cortisol synthase (CYP11B1). These compounds are unique among inhibitors of CYP11B2 in their lack of a strong-heme binding group such as a pyridine or imidazole. Poor metabolic stability in hepatocyte incubations was found to proceed via a reduction of the isoxazole ring. While the enzyme responsible for the reductive metabolism remains unknown, the rate of metabolism could be attenuated by the addition of polar functionality. The in vitro CYP11B2 potency and selectivity were confirmed in vivo in a cynomolgus monkey model by the inhibition of ACTH stimulated aldosterone production without impacting plasma cortisol concentrations.
Asunto(s)
Citocromo P-450 CYP11B2/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Isoxazoles/farmacología , Citocromo P-450 CYP11B2/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Isoxazoles/síntesis química , Isoxazoles/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) is regarded as a potential novel treatment for schizophrenic patients. Herein we report the synthesis and SAR of 4-aryl piperazine and piperidine amides as potent mGluR5 positive allosteric modulators (PAMs). Several analogs have excellent activity and desired drug-like properties. Compound 2b was further characterized as a PAM using several in vitro experiments, and produced robust activity in several preclinical animal models.
Asunto(s)
Amidas/química , Piperazinas/química , Piperidinas/química , Receptores de Glutamato Metabotrópico/química , Regulación Alostérica , Amidas/síntesis química , Amidas/uso terapéutico , Humanos , Microsomas Hepáticos/metabolismo , Piperazina , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC(50)=77 nM; µ:κ and δ:κ IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as well as good brain exposure. Analog 6c (κ IC(50)=20 nM; µ:κ=36, δ:κ=415) was also shown to reverse κ-agonist induced rat diuresis in vivo.
Asunto(s)
Benzamidas/química , Receptores Opioides kappa/antagonistas & inhibidores , Tropanos/química , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Línea Celular Tumoral , Diuresis/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Microsomas Hepáticos/metabolismo , Ratas , Receptores Opioides kappa/metabolismo , Relación Estructura-Actividad , Tropanos/síntesis química , Tropanos/farmacocinéticaRESUMEN
Further structure activity relationship studies on a previously reported 8-azabicyclo[3.2.1]octan-3-yloxy-benzamide series of potent and selective kappa opioid receptor antagonists is discussed. Modification of the pendant N-substitution to include a cyclohexylurea moiety produced analogs with greater in vitro opioid and hERG selectivity such as 12 (kappa IC50=172 nM, mu:kappa ratio=93, delta:kappa ratio=>174, hERG IC50=>33 microM). Changes to the linker conformation and identity as well as to the benzamide ring moiety were also investigated.