RESUMO
A series of dibasic des-hydroxy ß2 receptor agonists has been prepared and evaluated for potential as inhaled ultralong acting bronchodilators. Determination of activities at the human ß-adrenoreceptors demonstrated a series of highly potent and selective ß2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i.t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultralong acting inhaled ß2 receptor agonist with rapid onset of action.
RESUMO
Starting with the molecular scaffold of the DA(2)/ß(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full ß(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/química , Broncodilatadores/química , Receptores Adrenérgicos beta 2/química , Tiazóis/química , Agonistas de Receptores Adrenérgicos beta 2/síntese química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Animais , Broncodilatadores/síntese química , Broncodilatadores/farmacocinética , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Cobaias , Receptores Adrenérgicos beta 2/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
The design and synthesis of a new series of high efficacy ß(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious ß(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of ß(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Desenho de Fármacos , Agonistas de Receptores Adrenérgicos beta 2/química , Animais , Brônquios/citologia , Linhagem Celular , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.
Assuntos
Trifosfato de Adenosina/uso terapêutico , Adenosina/análogos & derivados , Proteínas de Membrana/antagonistas & inibidores , Antagonistas do Receptor Purinérgico P2 , Trombose/prevenção & controle , Adenosina/uso terapêutico , Administração Oral , Animais , Humanos , Receptores Purinérgicos P2Y12 , TicagrelorRESUMO
We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.