RESUMEN
Structural optimization of a previously reported agonist of µOR, PZM21 is described resulting in the discovery of a novel series of amides with at least 4-folds enhanced CNS penetration in rat. Furthermore, these efforts yielded compounds with varying levels of efficacy on the receptor ranging from high efficacy agonists such as compound 20 to antagonists, such as 24. The correlation between in vitro activation of µOR and relative activity in models of analgesia for these compounds is discussed. The compelling results obtained in these studies demonstrate the potential utility of these newly discovered compounds in the treatment of pain and opioid use disorder.
Asunto(s)
Trastornos Relacionados con Opioides , Dolor , Ratas , Animales , Dolor/tratamiento farmacológico , Amidas , Encéfalo/metabolismo , Receptores Opioides mu/agonistas , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéuticoRESUMEN
Tissue injury induces a long-lasting latent sensitization (LS) of spinal nociceptive signaling that is kept in remission by an opposing µ-opioid receptor (MOR) constitutive activity. To test the hypothesis that supraspinal sites become engaged, we induced hindpaw inflammation, waited 3 weeks for mechanical hypersensitivity to resolve, and then injected the opioid receptor inhibitors naltrexone, CTOP or ß-funaltrexamine subcutaneously, and/or into the cerebral ventricles. Intracerebroventricular injection of each inhibitor reinstated hypersensitivity and produced somatic signs of withdrawal, indicative of LS and endogenous opioid dependence, respectively. In naïve or sham controls, systemic naloxone (3 mg/kg) produced conditioned place aversion, and systemic naltrexone (3 mg/kg) increased Fos expression in the central nucleus of the amygdala (CeA). In LS animals tested 3 weeks after plantar incision, systemic naltrexone reinstated mechanical hypersensitivity and produced an even greater increase in Fos than in sham controls, particularly in the capsular subdivision of the right CeA. One third of Fos+ profiles co-expressed protein kinase C delta (PKCδ), and 35% of PKCδ neurons co-expressed tdTomato+ in Oprm1Cre ::tdTomato transgenic mice. CeA microinjection of naltrexone (1 µg) reinstated mechanical hypersensitivity only in male mice and did not produce signs of somatic withdrawal. Intra-CeA injection of the MOR-selective inhibitor CTAP (300 ng) reinstated hypersensitivity in both male and female mice. We conclude that MORs in the capsular subdivision of the right CeA prevent the transition from acute to chronic postoperative pain.
Asunto(s)
Núcleo Amigdalino Central , Hiperalgesia , Animales , Núcleo Amigdalino Central/metabolismo , Femenino , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/prevención & control , Masculino , Ratones , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Receptores Opioides , Receptores Opioides muRESUMEN
Opioid use disorder (OUD) is a major socioeconomic burden. An ideal OUD pharmacotherapy will mitigate the suffering associated with opioid-withdrawal, inhibit the effects of high efficacy opioids, and minimize opioid-cravings while being safe and accessible to a diverse patient population. Although current OUD pharmacotherapies inhibit the euphoric effects of opioids of abuse, the extent to which they safely alleviate withdrawal and opioid-cravings corresponds with their intrinsic µ opioid receptor (MOR) efficacy. In addition to inhibiting the euphoric effects of opioids of abuse, the medium efficacy MOR agonist buprenorphine alleviates withdrawal and opioid-cravings, but its intrinsic MOR efficacy is sufficient such that its utility is limited by abuse and safety liabilities. Although the MOR antagonist naltrexone minimizes euphoria and has no abuse liability, it exacerbates suffering associated with withdrawal and opioid cravings. Therefore, a therapeutic with intrinsic MOR activity between the partial agonist (buprenorphine) and the antagonist (naltrexone) would strike a balance between the benefits and liabilities of these two therapeutics. To address this need, we derived RM1490, an MOR agonist based on a nonmorphinan scaffold that exhibits approximately half the intrinsic MOR efficacy of buprenorphine. In a series of preclinical assays, we compared RM1490 with buprenorphine and naltrexone at doses that achieve therapeutic levels of central nervous system MOR occupancy. RM1490 exhibited a behavioral profile consistent with reduced reward, dependence, and precipitated withdrawal liabilities. RM1490 was also more effective than buprenorphine at reversing the respiratory depressant effects of fentanyl and did not suppress respiration when combined with diazepam. SIGNIFICANCE STATEMENT: In preclinical studies, RM1490 has a physiological and behavioral profile suitable for opioid use disorder maintenance therapy.
Asunto(s)
Trastornos Relacionados con Opioides , Buprenorfina , NaltrexonaRESUMEN
Chronic inflammatory pain is a major health problem worldwide with high prevalence in women. Cerebrolysin is a multimodal neuropeptide preparation that crosses the blood brain barrier and displays neuroprotective properties in aging and disease. Previously, we showed that cerebrolysin reduced mechanical allodynia in a model of persistent inflammation and pain. We aim to build upon the findings of our previous study by investigating the response to acute administration of cerebrolysin in two models of peripheral inflammation and assessing sex differences. We utilized the complete Freund's adjuvant (CFA) that produces maximal oedema and mechanical allodynia within days and carrageenan that produces similar effects within hours. Cerebrolysin reversed the mechanical allodynia in both sexes in CFA-treated rats. On the other hand, in rats treated with carrageenan, cerebrolysin was only effective in reducing mechanical allodynia in female rats. In conclusion, the present study shows that cerebrolysin effects may be sex-specific depending on different mechanisms that are at play in these two models of peripheral inflammatory pain. Further investigations are required to determine the factors contributing to sex differences.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Aminoácidos/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Edema/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Caracteres Sexuales , Dolor Agudo/inmunología , Animales , Carragenina , Dolor Crónico/inmunología , Modelos Animales de Enfermedad , Edema/inmunología , Femenino , Adyuvante de Freund , Hiperalgesia/inmunología , Inflamación , Masculino , Dimensión del Dolor , Ratas Wistar , Factores de TiempoRESUMEN
As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.
Asunto(s)
Descubrimiento de Drogas , Imidazoles/química , Imidazoles/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Perros , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Macaca fascicularis , Ratones , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Humanos , Masculino , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Based on their structural similarity to previously described compound AMG 009, indole-phenyl acetic acids were proposed to be potent dual inhibitors of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2) and prostanoid D receptor (DP or DP1). This series was equipotent to AMG 009 in binding assays against both receptors but exhibited decreased serum shift. We discovered early in the optimization of these indole-phenylacetic acid compounds that they demonstrated CYP3A4 time-dependent inhibition (TDI). Hypothesizing that the source of TDI was the indole core we modified the 1,2,3-substitution to eventually afford a highly potent modulator of CRTH2 and DP which did not exhibit TDI.
Asunto(s)
Citocromo P-450 CYP3A/metabolismo , Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Fenilacetatos/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Indoles/química , Estructura Molecular , Fenilacetatos/química , Relación Estructura-Actividad , Factores de TiempoRESUMEN
The discovery and optimization of novel N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamide GPR119 agonists is described. Modification of the pyridylphthalimide motif of the molecule with R(1)=-Me and R(2)=-(i)Pr substituents, incorporated with a 6-fluoro substitution on the central phenyl ring offered a potent and metabolically stable tool compound 22.
Asunto(s)
Descubrimiento de Drogas , Piridinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Sulfonamidas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Humanos , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Piridinas/química , Piridinas/metabolismo , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMEN
We describe the discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel agonists of GPR119. Previously described aniline 2 had suboptimal efficacy in signaling assays using cynomolgus monkey (cyno) GPR119 making evaluation of the target in preclinical models difficult. Replacement of the aniline ring with a tetrahydroquinoline ring constrained the rotation of the aniline C-N bond and gave compounds with increased efficacy on human and cyno receptors. Additional optimization led to the discovery of 10, which possesses higher free fraction in plasma and improved pharmacokinetic properties in rat and cyno compared to 2.
Asunto(s)
Descubrimiento de Drogas , Oxadiazoles/farmacología , Quinolinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Relación Dosis-Respuesta a Droga , Humanos , Macaca fascicularis , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Quinolinas/síntesis química , Quinolinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4-TTR interactions by our compounds through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compound in the series, showed concentration-dependent retinol and RBP4 lowering.
Asunto(s)
Descubrimiento de Drogas , Proteínas Plasmáticas de Unión al Retinol/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Ratas , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Vitamina A/sangreRESUMEN
We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.
Asunto(s)
Acetatos/farmacología , Descubrimiento de Drogas , Piperidonas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Sulfonamidas/química , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Acetatos/química , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Conformación Molecular , Piperidonas/química , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/química , Ratas , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/químicaRESUMEN
We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy)anilines as GPR119 agonists derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moieties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved pharmacokinetic (PK) properties.
Asunto(s)
Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Receptores Acoplados a Proteínas G/agonistas , Compuestos de Anilina/síntesis química , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Descubrimiento de Drogas , Humanos , Ratones , Modelos Moleculares , Receptores Acoplados a Proteínas G/química , Relación Estructura-ActividadRESUMEN
Low doses of µ-opioid receptor (MOR) agonists rapidly ameliorate symptoms in treatment-resistant obsessive-compulsive disorder (OCD) patients (10-50% of OCD patients). However, the utility of MOR agonists is limited by their safety liabilities. We developed a novel MOR partial agonist (EPD1540) that has an improved respiratory safety profile when compared to buprenorphine. Buprenorphine is a MOR partial agonist primarily used in the treatment of opiate-use disorder, which in investigator-led trials, has been shown to rapidly ameliorate symptoms in treatment-resistant OCD patients. In this study, we show that doses of EPD1504 and buprenorphine that occupy small fractions of MORs in the CNS (approximately 20%) are as effective as fluoxetine at ameliorating OCD-like behaviors in two different rat models (an operant probabilistic reversal task and marble burying). Importantly, effective doses of EPD1504 did not impair either locomotor activity, or respiration under normoxic or hypercapnic conditions. Additionally, EPD1504 had effects comparable to buprenorphine in the conditioned place preference assay. These results indicate that EPD1504 may provide a safer alternative to buprenorphine for the treatment of OCD patients.
RESUMEN
The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yield of the initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, a highly diastereoselective allylation, and a novel oxazoline-assisted piperidinone forming reaction to provide AM-8553 in 35.6% yield and 11 steps.
Asunto(s)
Acetatos/síntesis química , Antineoplásicos/síntesis química , Piperidonas/síntesis química , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Acetatos/química , Amino Alcoholes/síntesis química , Amino Alcoholes/química , Antineoplásicos/química , Ciclización , Humanos , Lactonas/síntesis química , Lactonas/química , Modelos Moleculares , Oxazoles/síntesis química , Oxazoles/química , Piperidonas/química , EstereoisomerismoRESUMEN
We have previously reported that optimization of a series of phenylacetic acid derivatives led to the discovery of CRTH2 and DP dual antagonists, such as AMG 009 and AMG 853. During the optimization process, we discovered that minor structural modifications also afforded potent and selective CRTH2 or DP antagonists. Here we report the structure-activity relationship that led to the discovery of selective CRTH2 antagonists such as 2 and 17, and selective DP antagonists, such as 4 and 5.
Asunto(s)
Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Asma/terapia , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Hipersensibilidad/tratamiento farmacológico , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Fenilacetatos/química , Fenilacetatos/farmacología , Prostaglandina D2/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
The discovery and initial optimization of a series of phenylalanine based agonists for GPR142 is described. The structure-activity-relationship around the major areas of the molecule was explored to give agonists 90 times more potent than the initial HTS hit in a human GPR142 inositol phosphate accumulation assay. Removal of CYP inhibition by exploration of the pyridine A-ring is also described.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Descubrimiento de Drogas , Hipoglucemiantes/farmacología , Fenilalanina/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Relación Dosis-Respuesta a Droga , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Fenilalanina/síntesis química , Fenilalanina/química , Ratas , Relación Estructura-ActividadRESUMEN
The optimization of a series of 8-aza-quinazolinone analogs for antagonist activity against the CXCR3 receptor is reported. Compounds were optimized to avoid the formation of active metabolites and time-dependent-inhibitors of CYP3A4. In addition, antagonists showed potent against CXCR3 activity in whole blood and optimized to avoid activity in the chromosomal aberration assay. Compound 25 was identified as having the optimal balance of CXCR3 activity and pharmacokinetic properties across multiple pre-clinical species, which are reported herein.
Asunto(s)
Quinazolinas/síntesis química , Quinazolinonas/síntesis química , Receptores CXCR3/antagonistas & inhibidores , Animales , Bleomicina/toxicidad , Aberraciones Cromosómicas , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Inflamación , Concentración 50 Inhibidora , Leucocitos/efectos de los fármacos , Macaca fascicularis , Ratones , Modelos Químicos , Quinazolinas/farmacología , Quinazolinonas/farmacología , Factores de TiempoRESUMEN
Our first generation CRTH2 and DP dual antagonists, represented by AMG 009, are more potent toward the CRTH2 receptor than to the DP receptor. Here we report our efforts in the discovery of CRTH2 and DP dual antagonists with more balanced potencies to both receptors, such as compound 15.
Asunto(s)
Diseño de Fármacos , Fenilacetatos/síntesis química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Células HEK293 , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Fenilacetatos/química , Fenilacetatos/farmacología , Unión Proteica/efectos de los fármacosRESUMEN
GPR142 is a novel GPCR that is predominantly expressed in pancreatic ß-cells. GPR142 agonists potentiate glucose-dependent insulin secretion, and therefore can reduce the risk of hypoglycemia. Optimization of our lead pyridinone-phenylalanine series led to a proof-of-concept compound 22, which showed in vivo efficacy in mice with dose-dependent increase in insulin secretion and a decrease in glucose levels.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Fenilalanina/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Glucemia/análisis , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Prueba de Tolerancia a la Glucosa , Células HEK293 , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Masculino , Ratones , Ratones Endogámicos , Microsomas/química , Fenilalanina/administración & dosificación , Fenilalanina/química , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-ActividadRESUMEN
The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of ß-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4'-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion in rodents.