Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Más filtros

Bases de datos
Tipo del documento
Intervalo de año de publicación
1.
J Med Chem ; 62(20): 9270-9280, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31532662

RESUMEN

GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.


Asunto(s)
Pirrolidinas/química , Sulfonamidas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Animales , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Pirrolidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Canales Catiónicos TRPV/metabolismo
2.
J Med Chem ; 61(24): 11209-11220, 2018 12 27.
Artículo en Inglés | MEDLINE | ID: mdl-30500190

RESUMEN

Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of transient receptor potential vanilloid-4 (TRPV4) cation channels may offer an alternative-and potentially superior-therapy. Efforts directed toward small-molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity, and pharmacokinetic properties are described. Activity of leading exemplars 19 and 27 in an in vivo model suggestive of therapeutic potential is highlighted herein.


Asunto(s)
Edema Pulmonar/tratamiento farmacológico , Pirrolidinas/farmacología , Sulfonamidas/farmacología , Sulfonas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonas/química , Sulfonas/farmacocinética
3.
J Med Chem ; 59(11): 5356-67, 2016 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-27167608

RESUMEN

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Pirazoles/farmacología , Tiazoles/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química
4.
J Med Chem ; 51(19): 5915-8, 2008 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-18798607

RESUMEN

A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.


Asunto(s)
Broncoconstricción/efectos de los fármacos , Broncodilatadores/farmacología , Piperazinas/farmacología , Receptores Muscarínicos/efectos de los fármacos , Administración Intranasal , Animales , Pruebas de Provocación Bronquial , Broncoconstrictores/farmacología , Broncodilatadores/síntesis química , Broncodilatadores/química , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Cloruro de Metacolina/farmacología , Ratones , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Estereoisomerismo , Relación Estructura-Actividad
5.
J Med Chem ; 51(16): 4866-9, 2008 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-18680280

RESUMEN

High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.


Asunto(s)
Antagonistas Muscarínicos/farmacología , Compuestos de Fenilurea/farmacología , Compuestos de Amonio Cuaternario/farmacología , Tirosina/análogos & derivados , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Broncoconstricción/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Cobayas , Ratones , Ratas , Tirosina/farmacología
6.
Bioorg Med Chem Lett ; 17(6): 1722-5, 2007 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-17267215

RESUMEN

High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.


Asunto(s)
Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Animales , Células CHO , Quimiotaxis de Leucocito/efectos de los fármacos , Simulación por Computador , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Indicadores y Reactivos , Proteína Quinasa de Distrofia Miotónica , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Receptores CCR8 , Relación Estructura-Actividad , Células Th2/efectos de los fármacos
7.
Bioorg Med Chem Lett ; 16(13): 3362-6, 2006 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-16650762

RESUMEN

A series of 1,3-disubstituted cyclohexylmethyl urea and amide derivatives were synthesized as motilin receptor antagonists. Starting from known motilin antagonists, 1a and 1b, the cyclopentene scaffold was replaced and the four recognition elements optimized to arrive at a potent novel series.


Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Ciclohexanos/química , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Urea/síntesis química , Urea/farmacología , Amidas/química , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Urea/química
8.
Bioorg Med Chem Lett ; 15(13): 3229-32, 2005 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-15936190

RESUMEN

High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that led to the identification of a truncated sub-series, represented by SB-436811 (1a), are described.


Asunto(s)
Pirrolidinas/síntesis química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Humanos , Pirrolidinas/farmacología , Estereoisomerismo , Relación Estructura-Actividad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA