RESUMEN
Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Perros , Humanos , Concentración 50 Inhibidora , Ratones , Microsomas Hepáticos/efectos de los fármacos , Simulación del Acoplamiento Molecular , RatasRESUMEN
A novel set of compounds containing a 4,5-dihydro-5-methylisoxazoline have been successfully designed as VLA-4 receptor antagonists. Compound (14p) had a high receptor binding affinity of 4 nM and also found to be metabolically stable in vitro.
Asunto(s)
Integrina alfa4beta1/antagonistas & inhibidores , Isoxazoles/química , Isoxazoles/farmacología , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Estabilidad de Medicamentos , Humanos , Integrina alfa4beta1/química , Isoxazoles/síntesis química , Unión Proteica , Relación Estructura-Actividad , Células U937RESUMEN
The synthesis and antibacterial activity of 1,2,4-triazolo[4,3-a]pyrimidine oxazolidinones is reported. Compound 3e with a 2,4-disubstituted thiophene ring was found to be a potent inhibitor of Gram-positive pathogens and was 4-16-fold more potent than Linezolid.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Oxazolidinonas/farmacología , Pirimidinas/farmacología , Triazoles/farmacología , Antibacterianos/química , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Modelos Moleculares , Estructura Molecular , Oxazolidinonas/síntesis química , Oxazolidinonas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
The synthesis and antibacterial activity of 3-(4-([1,2,4]triazolo[4,3-a]pyrimidin-3-yl)phenyl)oxazolidin-2-ones is reported. Thiocarbonyl derivatives were found to be potent inhibitors of gram-positive pathogens and compound 4l was two to fourfold more potent than Linezolid.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Pirimidinas/síntesis química , Acetamidas/química , Acetamidas/farmacología , Antibacterianos/química , Linezolid , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazolidinonas/química , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad , Tiocarbamatos/química , Tiocarbamatos/farmacologíaRESUMEN
RBx 343E48F0 is a novel, potent, selective and long acting muscarinic receptor antagonist with a potential for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD). The aim of the present study was to describe the in vitro and in vivo profile of RBx 343E48F0 and to compare the results with the present day benchmark therapy, tiotropium. Radioligand binding and isolated tissue based functional assays were used to evaluate the affinity, potency and receptor subtype selectivity of RBx 343E48F0. Inhibition of carbachol-induced bronchoconstriction in the anaesthetized rat and acetylcholine-induced bronchoconstriction in the conscious rat were used to assess the extent and duration of the bronchospasmolytic activity of RBx 343E48F0. In vitro and in vivo pharmacokinetic studies were conducted to evaluate the pharmacokinetic and lung retention properties of the compound. In vitro radioligand binding studies using human recombinant muscarinic receptors showed that RBx 343E48F0 had a pKi of 9.6 at the M(3) receptor and a 60-fold selectivity for the M(3) receptor over the M(2) receptor. In isolated tissue bioassays, it exhibited surmountable antagonism at the guinea pig trachea with a pK(B) of 9.5. Intratracheal administration to anaesthetized rats demonstrated a dose-dependent inhibition of carbachol-induced bronchoconstriction with an ED(50) value of 110 ng/kg. RBx 343E48F0 also exhibited a fast onset of action and long duration of action of greater 24h.
Asunto(s)
Imidazoles/farmacología , Imidazoles/farmacocinética , Antagonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/farmacocinética , Receptores Muscarínicos/metabolismo , Acetilcolina/farmacología , Animales , Broncoconstricción/efectos de los fármacos , Femenino , Cobayas , Humanos , Imidazoles/administración & dosificación , Imidazoles/metabolismo , Cloruro de Metacolina/farmacología , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/metabolismo , Ratas , Respiración Artificial , Especificidad por SustratoRESUMEN
A novel set of compounds with a 1,3-dioxolane ring which acts as a proline bioisostere have been successfully designed as VLA-4 receptor antagonists. Compounds (18e), (28j), and (35g) were shown to have high receptor affinities.
Asunto(s)
Dioxolanos/química , Dioxolanos/farmacología , Integrina alfa4beta1/antagonistas & inhibidores , Integrina alfa4beta1/metabolismo , Línea Celular , Dioxolanos/síntesis química , Humanos , Modelos Moleculares , Unión Proteica/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The Ser/Thr protein kinase MAPKAP kinase2 (MAPKAPK2 or MK2) plays an important role in inflammation. A comparison of several crystal structures of MK2 shows that differences in active and inactive conformations result in large part from structural variations within the conformations of the glycine rich loop (p-loop) regions. We propose the most preferred binding conformation of two classes of MK2 inhibitors and suggest plausible critical interactions with active site residues. The predicted binding conformations of the two classes of MK2 inhibitors depend upon their orientation in the active site and activities were well correlated with the sum of D and G scores. A qualitative relationship between the sum of D and G scores and the measured activities can be demonstrated.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/química , Modelos Moleculares , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/química , Pirazoles/metabolismo , Pirazoles/farmacología , Piridinas/metabolismo , Piridinas/farmacología , Adenosina Trifosfato/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Dominio Catalítico , Simulación por Computador , Secuencia Conservada , Cristalografía por Rayos X , Glicina , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ligandos , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Secundaria de Proteína , Pirazoles/química , Piridinas/química , Reproducibilidad de los ResultadosRESUMEN
We describe herein the discovery and development of a series of 4-arylthieno[3,2-d]pyrimidines which are potent adenosine A(2A) receptor antagonists. These novel compounds show high degrees of selectivity against the human A(1), A(2B) and A(3) receptor sub-types. Moreover, a number of these compounds show promising activity in vivo, suggesting potential utility in the treatment of Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/uso terapéutico , Diseño de Fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Pirimidinas/uso terapéutico , Antagonistas del Receptor de Adenosina A1 , Antagonistas del Receptor de Adenosina A3 , Antiparkinsonianos/síntesis química , Humanos , Modelos Químicos , Pirimidinas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of pyrazolo[3,4-d]pyrimidine, pyrrolo[2,3-d]pyrimidine and 6-arylpurine adenosine A(2A) antagonists is described. Many examples were highly selective against the human A(1) receptor sub-type and were active in an in vivo model of Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/uso terapéutico , Diseño de Fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Purinas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Antagonistas del Receptor de Adenosina A1 , Antiparkinsonianos/síntesis química , Humanos , Modelos Químicos , Purinas/síntesis química , Pirazoles/síntesis química , Pirimidinas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The (-)-(11R,2'S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A(2A) receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A(2A) receptor. These derivatives show selectivity against the A(1) receptor. Furthermore, some of these compounds have been shown to have in vivo activity in a commonly used model, suggesting the potential for the treatment of Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antimaláricos/uso terapéutico , Antiparkinsonianos/uso terapéutico , Trastornos Parkinsonianos/tratamiento farmacológico , Pirimidinas/uso terapéutico , Antimaláricos/síntesis química , Antiparkinsonianos/síntesis química , Humanos , Modelos Químicos , Pirimidinas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Several potent oxazolidinone antibacterial agents were obtained by systematic modification of the linker between the five-membered heterocycle and the piperazinyl ring of RBx 7644 (Ranbezolid, 1) and its thienyl analogue 2, leading to the identification of an expanded spectrum compound RBx 8700 (6b).
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Antibacterianos/química , Enterococcus faecium/efectos de los fármacos , Estructura Molecular , Oxazolidinonas/química , Staphylococcus aureus/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of constrained piperidine analogues were synthesized as novel muscarinic M(3) receptor antagonists. Evaluation of these compounds in binding assays revealed that they not only have high affinity for the M(3) receptor but also have high selectivity over the M(2) receptor.
Asunto(s)
Antagonistas Muscarínicos/síntesis química , Antagonistas Muscarínicos/farmacología , Receptor Muscarínico M3/antagonistas & inhibidores , Antagonistas Muscarínicos/química , Relación Estructura-ActividadRESUMEN
A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.