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
High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Progranulinas/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Proteínas Adaptadoras del Transporte Vesicular/antagonistas & inhibidores , Amidas/química , Amidas/metabolismo , Aminoácidos/química , Aminoácidos/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Ensayos Analíticos de Alto Rendimiento , Humanos , Simulación de Dinámica Molecular , Progranulinas/antagonistas & inhibidores , Unión Proteica , Pirazoles/química , Pirazoles/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo , 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
Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Trastornos Migrañosos/tratamiento farmacológico , Piridinas/síntesis química , Piridinas/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Administración Oral , Analgésicos/sangre , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Perros , Humanos , Macaca mulatta , Ratones , Piridinas/sangre , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Especificidad de la Especie , Compuestos de Espiro/sangreRESUMEN
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 previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same time predicting acceptable heterocycle positioning for related analogs. Subsequently, specific quinoline and naphthyridine compounds were prepared which supported these structural predictions by displaying CGRP binding affinities in the 0.037-0.15 nM range.
Asunto(s)
Amidas/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Amidas/química , EstereoisomerismoRESUMEN
A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Quinolinas/farmacología , Animales , Disponibilidad Biológica , Perros , Evaluación Preclínica de Medicamentos , Macaca mulatta , Quinolinas/química , Quinolinas/farmacocinética , RatasRESUMEN
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
A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure-activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K(+) channel. Preferred compounds were subsequently evaluated for selectivity in an alpha(1)-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.
Asunto(s)
Benzocicloheptenos/síntesis química , Neurotransmisores/síntesis química , Piridinas/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Benzocicloheptenos/química , Benzocicloheptenos/farmacología , Línea Celular , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Neurotransmisores/química , Neurotransmisores/farmacología , Piridinas/química , Piridinas/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Relación Estructura-ActividadRESUMEN
A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP Ki=0.035 nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved.
Asunto(s)
Acetamidas/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Compuestos de Espiro/química , Acetamidas/síntesis química , Acetamidas/farmacología , Animales , Línea Celular , Diseño de Fármacos , Humanos , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Indoles/síntesis química , Compuestos de Espiro/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Perros , Descubrimiento de Drogas , Humanos , Indoles/farmacología , Macaca mulatta , Oxindoles , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos de Espiro/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular , Perros , Haplorrinos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Compuestos de Espiro/administración & dosificaciónRESUMEN
Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiology of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack, and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clinical proof-of-concept in the acute treatment of migraine was demonstrated with an intravenous formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). Here we report on the pharmacological characterization of the first orally bioavailable CGRP receptor antagonist in clinical development, MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide]. In vitro, MK-0974 is a potent antagonist of the human (K(i) = 0.77 nM) and rhesus (K(i) = 1.2 nM) CGRP receptors but displays >1500-fold lower affinity for the canine and rat receptors as determined via (125)I-human CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concentration-dependent inhibition of dermal vasodilation, generated by capsaicin-induced release of endogenous CGRP, with plasma concentrations of 127 and 994 nM required to block 50 and 90% of the blood flow increase, respectively. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist, which may be valuable in the acute treatment of migraine.
Asunto(s)
Azepinas/administración & dosificación , Azepinas/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Imidazoles/administración & dosificación , Imidazoles/química , Trastornos Migrañosos/tratamiento farmacológico , Administración Oral , Animales , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Macaca mulatta , Masculino , Trastornos Migrañosos/metabolismo , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismoRESUMEN
In our effort to find potent, orally bioavailable CGRP receptor antagonists for the treatment of migraine, a novel series based on a pyridinone template was investigated. After optimizing the privileged structure and the placement of the attached phenyl ring, systematic SAR was carried out on both the N-alkyl and C-5 aryl substituents. Several analogs with good potency and pharmacokinetic profiles were identified.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Piridonas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Semivida , Piridonas/administración & dosificación , Piridonas/química , Piridonas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.
Asunto(s)
Amidas/farmacología , Antagonistas del Receptor de Bradiquinina B1 , Amidas/química , Amidas/farmacocinética , Animales , Disponibilidad Biológica , Barrera Hematoencefálica , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Semivida , Humanos , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure containing a (3R)-amino-(6S)-phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivatives with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clinical candidate 38 (MK-0974).
Asunto(s)
Azepinas/síntesis química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Imidazoles/síntesis química , Trastornos Migrañosos/tratamiento farmacológico , Administración Oral , Animales , Azepinas/farmacocinética , Azepinas/farmacología , Disponibilidad Biológica , Células CACO-2 , Permeabilidad de la Membrana Celular , Perros , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Macaca mulatta , Ratas , Flujo Sanguíneo Regional/efectos de los fármacos , Piel/irrigación sanguínea , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.
Asunto(s)
Analgésicos/síntesis química , Encéfalo/metabolismo , Pirimidinas/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Administración Oral , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Antiparkinsonianos/síntesis química , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Disponibilidad Biológica , Línea Celular , Perros , Femenino , Lóbulo Frontal/metabolismo , Humanos , Masculino , Dimensión del Dolor , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The preclinical pharmacodynamic and pharmacokinetic properties of 4-methylbenzyl (3S, 4R)-3-fluoro-4-[(Pyrimidin-2-ylamino) methyl] piperidine-1-carboxylate (CERC-301), an orally bioavailable selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC-301 dose selection in clinical trials of major depressive disorder. CERC-301 demonstrated high-binding affinity (K i, 8.1 nmol L(-1)) specific to GluN2B with an IC 50 of 3.6 nmol L(-1) and no off-target activity. CERC-301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED 50) of 0.3-0.7 mg kg(-1) (RO, 30-50%); increase in locomotor activity was observed at ED 50 of 2 mg kg(-1), corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L(-1), similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L(-1), respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first-in-human study in healthy males demonstrated a dose-proportional pharmacokinetic profile, with T max of ~1 h and t 1/2 of 12-17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.
RESUMEN
Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.
Asunto(s)
Analgésicos/síntesis química , Bencimidazoles/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Encéfalo/metabolismo , Calcio/metabolismo , Carragenina , Línea Celular , Perros , Femenino , Humanos , Hiperalgesia/sangre , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Técnicas In Vitro , Masculino , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiología , Relación Estructura-ActividadRESUMEN
Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK-3207 led to a series of analogues with enhanced CNS penetrance and a convenient chemical handle for introduction of a radiolabel. A number of (11)C-tracers were synthesized and evaluated in vivo, leading to the identification of [(11)C]8 ([(11)C]MK-4232), the first positron emission tomography tracer for the CGRP receptor.