RESUMEN
CONTEXT: Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis and fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist. OBJECTIVE: Our objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single-dose and 7-d elagolix administration to healthy premenopausal women. DESIGN: This was a first-in-human, double-blind, placebo-controlled, single- and multiple-dose study with sequential dose escalation. PARTICIPANTS: Fifty-five healthy, regularly cycling premenopausal women participated. INTERVENTIONS: Subjects were administered a single oral dose of 25-400 mg or placebo. In a second arm of the study, subjects received placebo or 50, 100, or 200 mg once daily or 100 mg twice daily for 7 d. Treatment was initiated on d 7 (+/-1) after onset of menses. MAIN OUTCOME MEASURES: Safety, tolerability, pharmacokinetics, and serum LH, FSH, and estradiol concentrations were assessed. RESULTS: Elagolix was well tolerated and rapidly bioavailable after oral administration. Serum gonadotropins declined rapidly. Estradiol was suppressed by 24 h in subjects receiving at least 50 mg/d. Daily (50-200 mg) or twice-daily (100 mg) administration for 7 d maintained low estradiol levels (17 +/- 3 to 68 +/- 46 pg/ml) in most subjects during late follicular phase. Effects of the compound were rapidly reversed after discontinuation. CONCLUSIONS: Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states.
Asunto(s)
Estradiol/metabolismo , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Gonadotropinas/metabolismo , Antagonistas de Hormonas/administración & dosificación , Hidrocarburos Fluorados/administración & dosificación , Pirimidinas/administración & dosificación , Administración Oral , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Regulación hacia Abajo/efectos de los fármacos , Estradiol/sangre , Femenino , Gonadotropinas/sangre , Gónadas/efectos de los fármacos , Gónadas/metabolismo , Antagonistas de Hormonas/efectos adversos , Antagonistas de Hormonas/farmacocinética , Humanos , Hidrocarburos Fluorados/efectos adversos , Hidrocarburos Fluorados/farmacocinética , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Placebos , Premenopausia/efectos de los fármacos , Premenopausia/metabolismo , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Adulto JovenRESUMEN
The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.
Asunto(s)
Descubrimiento de Drogas , Hidrocarburos Fluorados/farmacología , Pirimidinas/farmacología , Receptores LHRH/antagonistas & inhibidores , Animales , Células CACO-2 , Inhibidores del Citocromo P-450 CYP3A , Evaluación Preclínica de Medicamentos , Humanos , Hidrocarburos Fluorados/química , Hidrocarburos Fluorados/metabolismo , Macaca fascicularis , Masculino , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pirimidinas/química , Pirimidinas/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Factores de TiempoRESUMEN
A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia.
Asunto(s)
Bencilaminas/farmacología , Caquexia/tratamiento farmacológico , Piperazinas/farmacología , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Animales , Bencilaminas/síntesis química , Bencilaminas/química , Células CACO-2 , Carcinoma Pulmonar de Lewis , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Conformación Molecular , Piperazinas/síntesis química , Piperazinas/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Factores de Tiempo , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4.
Asunto(s)
Inhibidores del Citocromo P-450 CYP3A , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Receptores LHRH/antagonistas & inhibidores , Uracilo/análogos & derivados , Uracilo/síntesis química , Animales , Citocromo P-450 CYP3A , Haplorrinos , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Relación Estructura-Actividad , Uracilo/farmacocinéticaRESUMEN
A potent and selective antagonist of the melanocortin-4 receptor, 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.
Asunto(s)
Caquexia/tratamiento farmacológico , Piperazinas/síntesis química , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , beta-Alanina/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Caquexia/etiología , AMP Cíclico/metabolismo , Perros , Ingestión de Alimentos/efectos de los fármacos , Humanos , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Trasplante de Neoplasias , Neoplasias Experimentales/complicaciones , Piperazinas/farmacocinética , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , beta-Alanina/síntesis química , beta-Alanina/farmacocinética , beta-Alanina/farmacologíaRESUMEN
Suppression of the hypothalamic-pituitary-gonadal axis by peptides that act at the GnRH receptor has found widespread use in clinical practice for the management of sex-steroid-dependent diseases (such as prostate cancer and endometriosis) and reproductive disorders. Efforts to develop orally available GnRH receptor antagonists have led to the discovery of a novel, potent nonpeptide antagonist, NBI-42902, that suppresses serum LH concentrations in postmenopausal women after oral administration. Here we report the in vitro and in vivo pharmacological characterization of this compound. NBI-42902 is a potent inhibitor of peptide radioligand binding to the human GnRH receptor (K(i) = 0.56 nm). Tritiated NBI-42902 binds with high affinity (K(d) = 0.19 nm) to a single class of binding sites and can be displaced by a range of peptide and nonpeptide GnRH receptor ligands. In vitro experiments demonstrate that NBI-42902 is a potent functional, competitive antagonist of GnRH stimulated IP accumulation, Ca(2+) flux, and ERK1/2 activation. It did not stimulate histamine release from rat peritoneal mast cells. Finally, it is effective in lowering serum LH in castrated male macaques after oral administration. Overall, these data provide a benchmark of pharmacological characteristics required for a nonpeptide GnRH antagonist to effectively suppress gonadotropins in humans and suggest that NBI-42902 may have clinical utility as an oral agent for suppression of the hypothalamic-pituitary-gonadal axis.
Asunto(s)
Receptores LHRH/antagonistas & inhibidores , Timina/análogos & derivados , Administración Oral , Animales , Sitios de Unión , Unión Competitiva , Bloqueadores de los Canales de Calcio/farmacología , Línea Celular , Activación Enzimática/efectos de los fármacos , Hormona Liberadora de Gonadotropina/farmacología , Liberación de Histamina/efectos de los fármacos , Humanos , Fosfatos de Inositol/antagonistas & inhibidores , Fosfatos de Inositol/metabolismo , Ligandos , Hormona Luteinizante/sangre , Macaca , Masculino , Mastocitos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Orquiectomía , Receptores LHRH/metabolismo , Timina/administración & dosificación , Timina/metabolismo , Timina/farmacologíaRESUMEN
CONTEXT: Parenteral administration of peptide GnRH analogs is widely used in clinical practice for the suppression of pituitary gonadotropins. NBI-42902 is an orally available, high-affinity nonpeptide antagonist of the human GnRH receptor. OBJECTIVE: The objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropin secretion of NBI-42902 in postmenopausal women. DESIGN: This was a phase I, double-blind, placebo-controlled, single-dose study with sequential dose escalation. PARTICIPANTS: Fifty-six healthy, postmenopausal women were included. FSH levels were greater than 40 IU/liter, and body mass index was within 20% of ideal values for all subjects. INTERVENTIONS: Subjects were administered 5, 10, 25, 50, 75, 100, 150, or 200 mg NBI-42902 as an oral solution. MAIN OUTCOME MEASURES: Safety, tolerability, and serum LH and FSH concentrations were evaluated. RESULTS: NBI-42902 was well tolerated. Serum LH concentrations rapidly declined, and dose-dependent suppression was observed. Maximal change from baseline LH concentrations ranged from -19 +/- 5% in the 5-mg group to -55 +/- 2% in the 150-mg group. Suppression of FSH was less pronounced (-15 to -22% of baseline). NBI-42902 was rapidly absorbed after oral administration with a terminal elimination half-life ranging from 2.7 +/- 0.3 to 4.8 +/- 0.8 h. A clear relationship between plasma NBI-42902 concentrations and LH suppression was evident. CONCLUSIONS: Dose-dependent LH suppression was achieved by oral administration of a nonpeptide GnRH antagonist suggesting that compounds such as NBI-42902 may enable adjustable gonadotropin suppression as part of novel treatment strategies for benign gynecological conditions.
Asunto(s)
Hormona Luteinizante/antagonistas & inhibidores , Posmenopausia/sangre , Timina/análogos & derivados , Administración Oral , Anciano , Método Doble Ciego , Femenino , Humanos , Hormona Luteinizante/sangre , Persona de Mediana Edad , Timina/farmacocinética , Timina/farmacologíaRESUMEN
Antagonists of the corticotropin-releasing factor (CRF) neuropeptide should prove to be effective in treating stress and anxiety-related disorders. In an effort to identify antagonists with improved physicochemical properties, new tricyclic CRF(1) antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF(1) binding affinity, NBI 35965 (12a) was identified as a high-affinity antagonist with a pK(i) value of 8.5. Compound 12a proved to be a functional CRF(1) antagonist with pIC(50) values of 7.1 and 6.9 in the in vitro CRF-stimulated cAMP accumulation and ACTH production assays, respectively, and 12a also reduced CRF or stress induced ACTH production in vivo.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/síntesis química , Pirazoles/síntesis química , Piridinas/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Acenaftenos , Hormona Adrenocorticotrópica/biosíntesis , Animales , Células Cultivadas , Hormona Liberadora de Corticotropina/metabolismo , AMP Cíclico/biosíntesis , Diseño de Fármacos , Femenino , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Conformación Molecular , Adenohipófisis/citología , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Derivatives of 1-(4-amino-phenyl)-pyrrolidin-3-yl-amine and 6-(3-amino-pyrrolidin-1-yl)-pyridin-3-yl-amine were identified as potent and functionally active MCH-R1 antagonists. One compound with Ki = 2.3 nM demonstrated good oral bioavailability (32%) and in vivo efficacy in rats.
Asunto(s)
Piridinas/farmacología , Pirrolidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Peso Corporal , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Modelos Animales , Estructura Molecular , Piridinas/química , Piridinas/farmacocinética , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas , Ratas Wistar , Receptores de Somatostatina/metabolismo , Relación Estructura-ActividadRESUMEN
Further structure-activity relationship studies of a series of substituted uracils at the 1, 3, and 5 positions resulted in the discovery of several potent antagonists of the human gonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione (R-13b, NBI 42902) displayed subnanomolar binding affinity (K(i) = 0.56 nM) and was a potent functional antagonist (IC(50) = 3.0 nM in Ca(2+) flux assay) at the human GnRH receptor. It also bound to the monkey GnRH receptor with high affinity (K(i) = 3.9 nM). In addition, R-13bhad good plasma exposure in cynomolgus monkeys after oral administration, with a C(max) of 737 ng/mL and an AUC of 2392 ng/mL.h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.
Asunto(s)
Receptores LHRH/antagonistas & inhibidores , Timina/análogos & derivados , Timina/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Membranas/efectos de los fármacos , Membranas/metabolismo , Estructura Molecular , Orquiectomía , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Ratas , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-Actividad , Timina/química , Timina/farmacologíaRESUMEN
We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF(1) receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26 h exhibited good binding affinity at the human CRF(1) receptor with a K(i) value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF(1) receptor (IC(50) = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells (IC(50) = 20 nM). 26 h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26 h was orally bioavailable and able to penetrate into the brain. 26 h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF(1) receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26 h was developed into a clinical compound and exhibited efficacy in patients with major depression.
Asunto(s)
Diseño de Fármacos , Pirimidinas/química , Pirimidinas/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Hormona Adrenocorticotrópica/metabolismo , Animales , Hormona Liberadora de Corticotropina/farmacología , AMP Cíclico/metabolismo , Concentración 50 Inhibidora , Masculino , Ratones , Estructura Molecular , Pirimidinas/administración & dosificación , Pirimidinas/síntesis química , Ratas , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Relación Estructura-ActividadRESUMEN
In our efforts to identify potent CRF(1) antagonists with proper physicochemical properties, a series of 3-phenylpyrazolo[1,5-a]pyrimidines bearing polar groups, such as amino, hydroxyl, methoxy, sulfoxide, were designed and synthesized. Several positions of the core structure were identified, where a polar group was tolerated with slight reduction in receptor binding. NBI 30545 (18n) was found to have good binding affinity and potent antagonistic activity at the human CRF(1) receptor. Moreover, this compound had proper lipophilicity (log D = 2.78) and good solubility in water (>10mg/mL), and exhibited good plasma and brain exposure when given orally.