RESUMEN
A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure-activity observations. Initial exploration of the structure-activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.
RESUMEN
A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead.
Asunto(s)
Analgésicos/uso terapéutico , Benzamidas/uso terapéutico , Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/uso terapéutico , Piridinas/uso terapéutico , Receptores Purinérgicos P2X3/metabolismo , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/farmacocinética , Animales , Benzamidas/síntesis química , Benzamidas/química , Benzamidas/farmacocinética , Perros , Diseño de Fármacos , Interacciones Farmacológicas , Glucuronosiltransferasa/antagonistas & inhibidores , Semivida , Hiperbilirrubinemia/prevención & control , Estructura Molecular , Antagonistas del Receptor Purinérgico P2X/síntesis química , Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/farmacocinética , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 µM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Trastornos Migrañosos/tratamiento farmacológico , Oxazolidinonas/farmacología , Oxazolidinonas/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxazolidinonas/síntesis química , Oxazolidinonas/química , Ratas , Relación Estructura-ActividadRESUMEN
In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclinical candidate 30 (MK-2918).
Asunto(s)
Azepinas/síntesis química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Imidazoles/síntesis química , Imidazoles/farmacología , Analgésicos no Narcóticos/síntesis química , Analgésicos no Narcóticos/química , Analgésicos no Narcóticos/farmacología , Animales , Azepinas/química , Azepinas/farmacología , Disponibilidad Biológica , Caprolactama/química , Células Cultivadas , Perros , Humanos , Imidazoles/química , Concentración 50 Inhibidora , Macaca mulatta , Trastornos Migrañosos/tratamiento farmacológico , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.
Asunto(s)
Analgésicos/química , Piridinas/química , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Analgésicos/síntesis química , Analgésicos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Adyuvante de Freund/farmacología , Humanos , Hiperalgesia/tratamiento farmacológico , Piridinas/síntesis química , Piridinas/uso terapéutico , Ratas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismoRESUMEN
Several novel spiropiperidine-based CGRP receptor antagonists have been developed that maintain good potency and have reduced potential for metabolism.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Péptido Relacionado con Gen de Calcitonina/farmacología , Fragmentos de Péptidos/farmacología , Piperidinas/farmacología , Compuestos de Espiro/farmacología , Secuencia de Aminoácidos , Animales , Péptido Relacionado con Gen de Calcitonina/química , Dicroismo Circular , Clonación Molecular , Humanos , Datos de Secuencia Molecular , Fragmentos de Péptidos/química , Piperidinas/química , Unión Proteica , Transducción de Señal , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
Two novel routes have been developed to the (3 R,6 S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one 2 of the CGRP receptor antagonist clinical candidate telcagepant (MK-0974, 1). The first employs a ring-closing metathesis of the styrene 7 as the key reaction, while the second makes use of a highly diastereoselective Hayashi-Miyaura Rh-catalyzed arylboronic acid addition to nitroalkene 16. The latter route has been implemented to produce multigram quantities of telcagepant for extensive preclinical evaluation.