RESUMEN
Novel magnetic-activated carbon composites (MACs) were synthesized via coupling of a glucose-assisted hydrothermal pretreatment and subsequent thermal treatment using iron sludge and biological sludge. The adsorption properties of MACs for sulfonamide antibiotic removal from aqueous solution were investigated. Results revealed that the MACs had a high specific surface area with well-distributed magnetic nano-sized Fe3O4/Fe0 particles with a graphitic shell. This finding indicates that the ferric compounds in the iron sludge were not only converted into magnetic ferrite but also worked as activators for graphitization of the surrounding amorphous carbon. The pseudo-second-order kinetics and Langmuir models were shown to well fit sulfonamide antibiotic adsorption on the MACs. There was a high correlation between the kl·qm and physicochemical parameters of the sulfonamides. The three parameters are molecular polarizability, octanol-water partition coefficient, and solubility, respectively. The sulfonamide adsorption by the MACs was highly pH dependent. Hydrophobic interaction, π-π interaction, as well as electrostatic interaction, played dominant roles in the sulfonamide adsorption.
Asunto(s)
Aguas del Alcantarillado , Contaminantes Químicos del Agua , Adsorción , Antibacterianos , Carbón Orgánico , Hierro , Cinética , Fenómenos Magnéticos , SulfonamidasRESUMEN
Modulators of S1P1 have proven utility for the treatment of autoimmune disease and efforts to identify new agents with improved safety and pharmacokinetic parameters are ongoing. Several new S1P1 chemotypes were designed and optimized for potency and oral bioavailability. These new agents are characterized by a 'tricyclic fused indole array' and are highly potent agonists of the S1P1 receptor.
Asunto(s)
Diseño de Fármacos , Indoles/química , Receptores de Lisoesfingolípidos/agonistas , Animales , Perros , Semivida , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Ratones , Unión Proteica , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Lisoesfingolípidos/metabolismo , Relación Estructura-ActividadRESUMEN
APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.
RESUMEN
S1P1 is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P1 functional antagonists, with favorable pharmacokinetic and safety properties.
RESUMEN
Despite the development of a number of efficacious kinase inhibitors, the strategies for rational design of these compounds have been limited by target promiscuity. In an effort to better understand the nature of kinase inhibition across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using biochemical assays for inhibitory activity against 234 active human kinases and kinase complexes, representing all branches of the kinome tree. For our study we employed 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important as therapeutic targets and/or signal transduction regulators. Hierarchical clustering of these benchmark kinase inhibitors on the basis of their kinome activity profiles illustrates how they relate to chemical structure similarities and provides new insights into inhibitor specificity and potential applications for probing new targets. Using this broad dataset, we provide a framework for assessing polypharmacology. We not only discover likely off-target inhibitor activities and recommend specific inhibitors for existing targets, but also identify potential new uses for known small molecules.
Asunto(s)
Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Aurora Quinasas , Análisis por Conglomerados , Diseño de Fármacos , Receptores ErbB/antagonistas & inhibidores , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , MAP Quinasa Quinasa 4/antagonistas & inhibidores , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Reproducibilidad de los Resultados , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Quinasa Syk , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
Two series of fused tricyclic indoles were identified as potent and selective S1P(1) agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P(3) receptor in vitro, and correspondingly did not produce S1P(3) mediated bradycardia in telemeterized rat.
Asunto(s)
Factores Inmunológicos/química , Indoles/química , Receptores de Lisoesfingolípidos/agonistas , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Humanos , Factores Inmunológicos/farmacocinética , Factores Inmunológicos/uso terapéutico , Indoles/farmacocinética , Indoles/uso terapéutico , Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Lisoesfingolípidos/metabolismo , Relación Estructura-ActividadRESUMEN
S1P(1) receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P(1) receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P(1) receptor agonists.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Butiratos/síntesis química , Butiratos/farmacología , Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Indoles/síntesis química , Indoles/farmacología , Linfocitos/metabolismo , Proteínas del Tejido Nervioso/agonistas , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Proteínas de Unión al ARN/agonistas , Animales , Butiratos/farmacocinética , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Haplorrinos , Ensayos Analíticos de Alto Rendimiento , Humanos , Inmunosupresores/farmacocinética , Indoles/farmacocinética , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas del Tejido Nervioso/química , Oxadiazoles/farmacocinética , Proteínas de Unión al ARN/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Inferring the relative bioactive poses between active molecules is a common problem in drug discovery. The use of rapid pairwise alignment algorithms in conjunction with rigid conformer libraries has become a prevalent approach to this problem. These programs can be easily used to compare two molecules or suggest alternatives to a single known active. However, it is not obvious how to combine pairwise alignments between multiple actives into an overlay that reproduces the binding mode of those actives in the target receptor. We describe a new algorithm, DIFGAPE (DIstance geometry Focused Genetic Algorithm Pose Evaluator) that, given pairwise alignments of conformers of active compounds, attempts to reproduce overlays of ligand binding modes. The software was evaluated on 13 test systems from 9 protein targets using associated ligands extracted from the PDB. Starting from 2D ligand structures with no protein information, we were able in 4 systems to approximate the crystallographically observed binding mode. For example, the prediction for a set of 11 ligands targeting FXa had 1.6 A rmsd to crystal structure coordinates. Finally, the evaluation illustrated current challenges for molecular conformer generators and pairwise alignment algorithms.
Asunto(s)
Algoritmos , Descubrimiento de Drogas , Proteínas/metabolismo , Animales , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Unión Proteica , Conformación Proteica , Proteínas/químicaRESUMEN
The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
Asunto(s)
Inhibidores del Citocromo P-450 CYP2D6 , Indanos/síntesis química , Indanos/farmacología , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/antagonistas & inhibidores , Clorhidrato de Atomoxetina , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Indanos/química , Concentración 50 Inhibidora , Microsomas Hepáticos/metabolismo , Estructura Molecular , Inhibidores de la Captación de Neurotransmisores/química , Propilaminas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The design, synthesis, and SAR of a series of ring-constrained norepinephrine reuptake inhibitors are described. A substantially rigid inhibitor with potent functional activity at the transporter (IC(50)=8 nM) was used to develop a model for the distance and orientation of key features necessary for interaction with the norepinephrine transporter (NET).
Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación Adrenérgica/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/síntesis química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/farmacología , Aminas/química , Clorhidrato de Atomoxetina , Sitios de Unión , Línea Celular , Química Farmacéutica/métodos , Desipramina/química , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Propilaminas/química , Relación Estructura-ActividadRESUMEN
This paper describes the application of de novo design utilizing exclusively ligand information. In the current approach, ligand design criteria, including pharmacophores, similarity and desired properties are applied as part of a fitness function driving the design process, instead of using them as filters after the process. This allows relevant parts of chemical space to be explored more efficiently. Two case studies of successful ligand design are also presented, one aimed at scaffold hopping, the other for exploring substitution patterns around a novel scaffold.
Asunto(s)
Diseño Asistido por Computadora , Diseño de Fármacos , Algoritmos , Humanos , Ligandos , Inhibidores de la Captación de Neurotransmisores , Receptores de GonadotropinaRESUMEN
OBJECTIVE: To explore the role of hepatitis C virus core protein on the infiltration and metastasis of cholangiocarcinoma tissues. METHODS: From January 2001 to November 2006, 34 patients with cholangiocarcinoma who had intact follow-up data randomly were chosen. The expression of HCVc protein, epithelium markers and mesenchymal markers in cholangiocarcinoma tissues were examined by SP methods of immunohistochemistry, clinical-pathological data were recorded and analyzed. RESULTS: The positive expression rate was observed in 47.1% for HCVc protein, 50% for N-cadherin, 44.1% for Vimentin, 55.9% for Fibronectin and the decreased expression rate was E-cadherin for 55.9%, alpha-catenin for 70.6%, beta-catenin for 55.9%. The positive expression of HCVc protein was associated with the decreased expression of E-cadherin, alpha-catenin and the positive expression of N-cadherin, Vimentin, Fibronectin (chi(2) = 4.480, 4.163, 4.250, 7.438, 12.260, P < 0.05). A positive-correlation between the expression of HCVc protein and metastasis of lymph nodes and other organs were found (chi(2) = 5.708, 4.163, P < 0.05). CONCLUSION: HCVc protein might promote cholangiocarcinoma tissues' infiltration and metastasis by inducing it's epithelial-mesenchymal transition.
Asunto(s)
Transformación Celular Neoplásica , Colangiocarcinoma/patología , Epitelio/patología , Proteínas del Núcleo Viral/fisiología , Adulto , Anciano , Colangiocarcinoma/metabolismo , Colangiocarcinoma/virología , Epitelio/metabolismo , Epitelio/virología , Femenino , Hepacivirus/metabolismo , Hepatitis C/metabolismo , Hepatitis C/patología , Hepatitis C/virología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteínas del Núcleo Viral/metabolismoRESUMEN
Nonpeptide antagonists of the human gonadotropin-releasing hormone receptor (GnRH-R) have been the subject of considerable interest because of their potential as a new class of oral therapeutics for the treatment of sex hormone-dependent diseases and infertility. While many classes of competitive GnRH-R antagonists have been described, we present here the first characterization of an allosteric nonpeptide GnRH-R antagonist. Previously, 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylmethyl)furan-2-carboxylic acid (2,4,6-trimethoxyphenyl)amide (here called Furan-1) had been demonstrated to be a potent GnRH-R antagonist both in vitro and in vivo. Using mutagenesis, the binding sites for Furan-1 and another potent nonpeptide antagonist (NBI-42902) have been mapped and are shown to be adjacent but nonoverlapping. Furan-1 is shown to affect the binding kinetics of radiolabeled peptide agonists as well as radiolabeled NBI-42902, and the kinetic data fit the allosteric ternary complex model. Furan-1 is considerably negatively cooperative with the nonpeptide antagonist and extremely negatively cooperative with the peptide agonist [125I-His5,d-Tyr6]GnRH so that it is nearly indistinguishable from an orthosteric competitive compound. Taken together, these data were used to develop a model of the nonpeptides bound to the GnRH-R binding site consistent with the current data.
Asunto(s)
Furanos/metabolismo , Antagonistas de Hormonas/metabolismo , Receptores LHRH/antagonistas & inhibidores , Receptores LHRH/metabolismo , Timina/análogos & derivados , Regulación Alostérica/genética , Animales , Sitios de Unión/genética , Unión Competitiva/genética , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Furanos/farmacología , Humanos , Concentración 50 Inhibidora , Mutagénesis Sitio-Dirigida , Ensayo de Unión Radioligante , Ratas , Receptores LHRH/agonistas , Receptores LHRH/genética , Estereoisomerismo , Timina/metabolismo , Timina/farmacologíaRESUMEN
We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302((7.32)) and H306((7.36)) suggest that these residues are part of a hydrogen-bond network important for anchoring the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with a trans conformational preference bind with high affinity and are sensitive to D302((7.32)) mutations. Another interaction area was found between the N-benzyl-N-methylamino substituent and L300((6.68)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.
Asunto(s)
Modelos Moleculares , Pirimidinas/síntesis química , Receptores LHRH/antagonistas & inhibidores , Receptores LHRH/química , Tiofenos/síntesis química , Secuencia de Aminoácidos , Animales , Unión Competitiva , Células COS , Chlorocebus aethiops , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Estructura Secundaria de Proteína , Pirimidinas/química , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Receptores LHRH/genética , Homología de Secuencia de Aminoácido , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
A new consensus approach has been developed for ligand-based virtual screening. It involves combining highly disparate properties in order to improve performance in virtual screening. The properties include structural, 2D pharmacophore and property-based fingerprints, scores derived using BCUT descriptors, and 3D pharmacophore approaches. Different approaches for the combination of all or some of these methods have been tested. Logistic regression and sum ranks were found to be the most advantageous in different pharmaceutical applications. The three major reasons consensus scoring appears to enrich data sets better than single scoring functions are (1) using multiple scoring functions is similar to repeated samplings, in which case the mean is closer to the true value than any single value, (2) due to the better clustering of actives, multiple sampling will recover more actives than inactives, and (3) different methods seem to agree more on the ranking of the actives than on the inactives. Furthermore, consensus results are not only better but are also more consistent across receptor systems.
RESUMEN
G protein-coupled receptors (GPCRs) are heptahelical integral membrane proteins that require cell surface expression to elicit their effects. The lack of appropriate expression of GPCRs may be the underlying cause of a number of inherited disorders. There is evidence that newly synthesized GPCRs must attain a specific conformation for their correct trafficking to the cell surface. In this study, we show that a single point mutation in human melanin-concentrating hormone receptor (hMCHR1) at position 255 (T255A), which is located at the junction of intracellular loop 3 and transmembrane domain 6, reduces the hMCHR1 cell surface expression level to 20% of that observed for the wild-type receptor. Most of these mutant receptors are located intracellularly, as opposed to the wild-type receptor, which is located primarily on the cell surface. Immunoprecipitation experiments show that hMCHR1-T255A has reduced glycosylation compared with the wild-type receptor and is associated with the chaperone protein, calnexin, and it colocalizes in the endoplasmic reticulum with KDEL-containing proteins. We also demonstrate that a cell-permeable small molecule antagonist of hMCHR1 can function as a pharmacological chaperone to restore cell surface expression of this and other MCHR1 mutants to wild-type levels. Once rescued, the T255A mutant couples to Gq proteins as efficiently as the wild-type receptor. These data suggest that this single mutation produces an hMCHR1 that folds incorrectly, resulting in its retention in the endoplasmic reticulum, but once rescued to the cell surface can still function normally.
Asunto(s)
Hormonas Hipotalámicas/metabolismo , Melaninas/metabolismo , Hormonas Hipofisarias/metabolismo , Mutación Puntual , Receptores de Somatostatina/química , Receptores de Somatostatina/genética , Secuencia de Aminoácidos , Transporte Biológico Activo , Línea Celular , Membrana Celular/metabolismo , Retículo Endoplásmico/metabolismo , Expresión Génica , Glicosilación , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Pliegue de Proteína , Estructura Terciaria de Proteína , Receptores de Somatostatina/antagonistas & inhibidores , Receptores de Somatostatina/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , TransfecciónRESUMEN
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
Recent studies have demonstrated that melanocortin-4 receptor (MC4R) antagonists can prevent weight loss in tumor-bearing mice, which indicates clinical usage for the treatment of cachexia. In our efforts to develop potent and selective antagonists of the human MC4R, we designed piperazinebenzylamines bearing a 2,4-dichlorophenylalanine, by utilizing information derived from structure--activity relationships of MC4R agonists and mutagenesis results of the MC4R and peptide ligands. On the basis of known MC4R agonists such 6, we successfully synthesized potent MC4R antagonists exemplified by 10, which possesses a K(i) value of 1.8 nM in binding affinity. 10 does not stimulate cAMP release in HEK 293 cells expressing the human MC4 receptor at 10 microM concentration. It was demonstrated by Schild analysis that 10 was a competitive functional antagonist with a pA(2) value of 7.9 in the inhibition of alpha-MSH-stimulated cAMP accumulation. 10 also penetrated into the brain when dosed intravenously in rats.
Asunto(s)
Caquexia/tratamiento farmacológico , Diseño de Fármacos , Piperazinas/síntesis química , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Tiofenos/síntesis química , Animales , AMP Cíclico/biosíntesis , Humanos , Masculino , Hormonas Estimuladoras de los Melanocitos/química , Ratones , Modelos Moleculares , Mutagénesis , Piperazinas/farmacología , Receptor de Melanocortina Tipo 4/genética , Receptor de Melanocortina Tipo 4/metabolismo , Tiofenos/farmacologíaRESUMEN
Uracils possessing N-3 side chains derived from various amino alcohols were designed and synthesized as potent human gonadotropin releasing hormone receptor antagonists. The compounds herein presented displayed superior metabolic stability than their predecessor molecules. Selected compounds from this series featured good oral bioavailability in mice and cynomolgus monkeys.
Asunto(s)
Receptores de HL/antagonistas & inhibidores , Uracilo/análogos & derivados , Uracilo/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Macaca fascicularis , Ratones , Estereoisomerismo , Relación Estructura-Actividad , Uracilo/farmacologíaRESUMEN
Based on the SAR from bicyclic gonadotropin-releasing hormone (GnRH) antagonists such as 6-aminomethyl-7-aryl-pyrrolo[1,2-a]pyrimid-4-ones (5) and 2-aryl-3-aminomethyl-imidazolo[1,2-a]pyrimid-5-ones (6a,b), a series of novel uracil compounds (8) were derived as GnRH antagonists. The synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed herein. Introduction of a small methyl substituent at the beta-position of the N3 side-chain improved the GnRH binding potency by 5-10-fold. Introduction of a methyl group of (R)-configuration at the alpha-carbon of the N-3 side-chain gave a modest improvement in binding affinity over the unsubstituted ethylene analogues. This modification enabled us to make uracil compounds without the labile 2-pyridylethyl motif on the basic nitrogen while still maintained excellent potency against the hGnRH receptor.